{"gene":"CCT6A","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1994,"finding":"CCT6A (Tcp20) is a subunit of the eukaryotic TRiC (TCP ring complex) chaperonin hetero-oligomeric complex, as demonstrated by gel filtration followed by Western analysis of purified bovine testis TRiC with a Tcp20-specific antibody. Gene disruption in yeast showed TCP20 is an essential gene, consistent with TRiC being required for folding of key proteins.","method":"Gel filtration + Western blotting of purified bovine TRiC; yeast gene disruption","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical isolation of the complex from purified protein, combined with genetic essentiality demonstrated by gene disruption","pmids":["8034610"],"is_preprint":false},{"year":2000,"finding":"CCT6A protein is widely expressed across mammalian tissues (kidney, liver, testes, lymphocytes, reticulocytes, cultured cell lines) and the ATP-binding sites are perfectly conserved among mammals and yeast, supporting a role in ATP-dependent protein folding.","method":"Western blotting with polyclonal anti-human CCT6 antibody; cDNA cloning and sequence analysis","journal":"Experimental nephrology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct protein detection across tissues by Western blot combined with sequence conservation analysis, single lab","pmids":["10810232"],"is_preprint":false},{"year":2013,"finding":"Progesterone activates CCT6A transcription in chicken granulosa cells via a progesterone response element (PRE) located in the distal promoter (−2056 to −2051), while FSH inhibits CCT6A mRNA expression; identified by promoter deletion and mutant constructs.","method":"Promoter deletion constructs, site-directed mutagenesis, reporter assays in granulosa cells","journal":"General and comparative endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection with deletion and mutation analysis, single lab","pmids":["23644154"],"is_preprint":false},{"year":2017,"finding":"CCT6A directly binds SMAD2 protein and acts as an inhibitor of SMAD2 function in non-small-cell lung carcinoma (NSCLC) cells. CCT6A-mediated suppression of SMAD2 (with SMAD3 intact) switches TGF-β-induced transcriptional responses toward a prometastatic state and promotes metastasis.","method":"Co-immunoprecipitation (direct binding), NSCLC cell lines, animal metastasis models, clinical specimens; selective SMAD3/CCT6A inhibition experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for direct binding, functional rescue in cell lines and animal models, corroborated with clinical specimens","pmids":["28375158"],"is_preprint":false},{"year":2022,"finding":"HOXB2 transcription factor directly binds the CCT6A promoter and upregulates CCT6A expression in colon cancer cells, placing HOXB2 upstream of CCT6A in a transcriptional regulatory axis that controls colon cancer proliferation, migration, and invasion.","method":"Luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), CCT6A knockdown and HOXB2 overexpression cell lines","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP and luciferase reporter confirm direct promoter binding, functional rescue experiment, single lab","pmids":["35315492"],"is_preprint":false},{"year":2024,"finding":"CCT6A interacts with STAT1 protein and protects it from ubiquitin-mediated degradation, thereby enhancing STAT1 stability. Stabilized STAT1 then facilitates transcription of hexokinase 2 (HK2), promoting aerobic glycolysis in lung adenocarcinoma cells.","method":"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), transcriptomic sequencing, liquid chromatography-mass spectrometry, CCT6A silencing","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding, ChIP for HK2 transcriptional activation, multiple orthogonal methods, single lab","pmids":["38750462"],"is_preprint":false},{"year":2024,"finding":"CCT6A directly binds both wild-type p53 (Wtp53) and mutant p53 (Mutp53), and regulates BIRC5 (survivin) expression through distinct p53-dependent and p53-independent pathways in colon cancer cells; CCT6A inhibition reduces BIRC5 expression independently of Wtp53 levels in Wtp53 cells, whereas in Mutp53 cells it mainly depends on Mutp53 levels.","method":"Co-immunoprecipitation for direct CCT6A-p53 binding; CCT6A silencing with p53 status-dependent functional readouts in vitro and in vivo","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding shown by Co-IP, functional pathway dissection in isogenic contexts, single lab","pmids":["38997438"],"is_preprint":false},{"year":2025,"finding":"TRIM38 E3 ubiquitin ligase directly binds CCT6A and promotes its K48-linked ubiquitination at K127/K138 residues, leading to proteasomal degradation of CCT6A. Reduced CCT6A levels in turn diminish stabilization of c-Myc protein, suppressing the MYC pathway in colorectal cancer.","method":"Co-immunoprecipitation for TRIM38-CCT6A binding; ubiquitination assays; mutagenesis of K127/K138 residues; functional tumor suppression assays in vitro and in vivo","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding by Co-IP, site-specific ubiquitination demonstrated by mutagenesis, functional rescue, in vivo validation","pmids":["40047371"],"is_preprint":false},{"year":2025,"finding":"CCT6A secreted by cancer-associated fibroblasts (CAFs) is transferred to gastric cancer cells via exosomes, where it interacts with β-catenin, inducing β-catenin phosphorylation and nuclear translocation. This activates c-Myc-mediated transcriptional suppression of glycolysis inhibitors DDIT4 and TXNIP, enhancing stemness, chemoresistance, and glycolysis.","method":"Co-culture system of CAFs and cancer cells; exosomal transfer experiments; Co-immunoprecipitation for CCT6A–β-catenin interaction; Western blot and nuclear fractionation for β-catenin translocation; ceRNA/pseudogene regulatory circuit analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for β-catenin binding, exosomal transfer experimentally demonstrated, multiple functional readouts, single lab","pmids":["40801472"],"is_preprint":false},{"year":2025,"finding":"PDAC-derived exosomal CCT6A promotes M2 polarization of tumor-associated macrophages via PI3K-AKT signaling. CCT6A interacts with chemokines (CXCL1, CXCL3, CCL20, CCL5) in PDAC cells (confirmed by interactomics), and exosomal CCT6A transfers these chemokines to TAMs; silencing CCT6A abrogated tumor immunosuppression and sensitized PDAC to CD47 antibody immunotherapy in vivo.","method":"Intratumoral injection of exosomes in C57BL/6 mice; multi-omics (proteomics, interactomics); CCT6A silencing in vivo; co-culture experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — interactomics for chemokine binding, exosome delivery functionally validated in vivo, multi-omics, single lab","pmids":["40374617"],"is_preprint":false},{"year":2024,"finding":"CCT6A interacts with RPS3 (ribosomal protein S3) in hepatocellular carcinoma cells with high metastatic potential, and this interaction may potentiate HCC metastasis by affecting metabolic processes. Gain- and loss-of-function analyses confirmed CCT6A promotes HCC migration and invasion.","method":"Co-immunoprecipitation for CCT6A-RPS3 interaction; gain/loss-of-function migration and invasion assays","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for binding, mechanistic link to metastasis not fully resolved, single lab","pmids":["39630318"],"is_preprint":false},{"year":2024,"finding":"In cervical cancer cells, CCT6A silencing reduces telomerase activity by inhibiting the interaction between telomerase assembly factor TCAB1 and TERT. TERT in turn activates the HK2 gene promoter; thus CCT6A promotes glycolysis under hypoxia via the TCAB1/TERT/HK2 axis.","method":"Immunofluorescence for protein localization; co-immunoprecipitation for TCAB1-TERT interaction; CCT6A siRNA knockdown; TERT inhibition and HK2 promoter transcription assay; nude mouse xenograft model","journal":"Gynecologic and obstetric investigation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for TCAB1-TERT interaction, promoter transcription assay, in vivo validation, single lab","pmids":["38657573"],"is_preprint":false},{"year":2023,"finding":"In esophageal squamous cell carcinoma (ESCC) cells, CCT6A promotes cell proliferation, invasion, and EMT by activating the TGF-β/Smad/c-Myc pathway; CCT6A knockdown decreased p-Smad2, p-Smad3, and c-Myc expression, while TGF-β treatment compensated for the effects of CCT6A knockdown.","method":"CCT6A siRNA knockdown and overexpression; TGF-β rescue experiment; Western blot for p-Smad2, p-Smad3, c-Myc; cell proliferation, apoptosis, and invasion assays","journal":"Irish journal of medical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation inferred from downstream marker changes and TGF-β rescue, no direct binding demonstrated between CCT6A and pathway components, single lab","pmids":["37017854"],"is_preprint":false},{"year":2025,"finding":"CCT6A promotes colon cancer cell proliferation, migration, and invasion by increasing cleavage of latency-associated peptide (LAP)-TGF-β1 to its mature form and inducing Smad2/3 phosphorylation, as well as by modulating fatty acid synthesis.","method":"Western blot for LAP-TGF-β1 cleavage and p-Smad2/3; CCT6A knockdown/overexpression; BODIPY staining for lipid droplets; nude mouse model","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanism inferred from downstream readouts without direct binding evidence between CCT6A and TGF-β1, single lab","pmids":["41399140"],"is_preprint":false}],"current_model":"CCT6A is the zeta subunit of the hetero-oligomeric TRiC/CCT chaperonin complex that mediates ATP-dependent folding of cytoplasmic proteins (including actin, tubulin, and others); beyond this canonical chaperonin role, CCT6A acts as a direct binding inhibitor of SMAD2 to rewire TGF-β signaling toward prometastasis, is ubiquitinated at K127/K138 by TRIM38 for proteasomal degradation, stabilizes STAT1 from ubiquitin-mediated degradation to drive HK2-dependent glycolysis, interacts with β-catenin to promote nuclear translocation and c-Myc activation, and can be transferred via exosomes from stromal or tumor cells to modulate the tumor microenvironment."},"narrative":{"mechanistic_narrative":"CCT6A (Tcp20) is the zeta subunit of the eukaryotic TRiC/CCT chaperonin, a hetero-oligomeric complex required for ATP-dependent folding of cytoplasmic proteins, and its gene is essential in yeast [PMID:8034610]. It is broadly expressed across mammalian tissues with ATP-binding sites conserved from yeast to mammals, consistent with this folding role [PMID:10810232]. Beyond the canonical chaperonin function, CCT6A acts in cancer as a direct protein-binding partner that rewires signaling: it binds SMAD2 and selectively inhibits SMAD2 function, switching TGF-β-induced transcription toward a prometastatic program in non-small-cell lung carcinoma [PMID:28375158], and it binds STAT1 to protect it from ubiquitin-mediated degradation, stabilizing STAT1 to drive transcription of hexokinase 2 (HK2) and aerobic glycolysis [PMID:38750462]. CCT6A also directly binds both wild-type and mutant p53 to regulate BIRC5/survivin through p53-dependent and p53-independent routes [PMID:38997438]. CCT6A protein levels are controlled by the E3 ligase TRIM38, which directly binds CCT6A and catalyzes K48-linked ubiquitination at K127/K138 to target it for proteasomal degradation; loss of CCT6A reduces c-Myc stabilization and suppresses the MYC pathway [PMID:40047371]. CCT6A is secreted via exosomes from stromal and tumor cells, where transferred CCT6A interacts with β-catenin to promote its nuclear translocation and c-Myc-driven transcriptional programs supporting stemness, chemoresistance, and glycolysis [PMID:40801472].","teleology":[{"year":1994,"claim":"Established that CCT6A is a bona fide subunit of the TRiC/CCT chaperonin and that the gene is essential, defining its foundational role in cytoplasmic protein folding.","evidence":"Gel filtration plus Western blotting of purified bovine testis TRiC with a Tcp20-specific antibody, and yeast TCP20 gene disruption","pmids":["8034610"],"confidence":"High","gaps":["Does not map which client proteins depend on the CCT6A subunit specifically","No structural detail on CCT6A's position within the ring"]},{"year":2000,"claim":"Showed CCT6A is widely expressed and its ATP-binding sites are evolutionarily conserved, supporting a general role in ATP-dependent folding across mammalian tissues.","evidence":"Western blotting with anti-human CCT6 antibody across tissues; cDNA cloning and sequence analysis","pmids":["10810232"],"confidence":"Medium","gaps":["Expression survey does not demonstrate tissue-specific function","ATP-binding sites inferred from sequence, not measured biochemically"]},{"year":2013,"claim":"Identified hormonal transcriptional control of CCT6A, with progesterone activating and FSH inhibiting its expression via a defined promoter element.","evidence":"Promoter deletion and site-directed mutagenesis reporter assays in chicken granulosa cells","pmids":["23644154"],"confidence":"Medium","gaps":["Performed in chicken granulosa cells; mammalian relevance not established","Functional consequence of CCT6A induction not assayed"]},{"year":2017,"claim":"Defined a non-canonical CCT6A function as a direct SMAD2 binder that selectively inhibits SMAD2 to redirect TGF-β signaling toward metastasis, distinguishing it from a pure folding role.","evidence":"Reciprocal Co-IP, NSCLC cell lines, animal metastasis models, and clinical specimens with selective SMAD3/CCT6A inhibition","pmids":["28375158"],"confidence":"High","gaps":["Does not resolve how CCT6A discriminates SMAD2 from SMAD3","Relationship of this moonlighting role to the TRiC complex unclear"]},{"year":2022,"claim":"Placed CCT6A downstream of HOXB2 in a transcriptional axis driving colon cancer progression, establishing an upstream regulator of CCT6A expression.","evidence":"ChIP and luciferase reporter for direct HOXB2 promoter binding; CCT6A knockdown and HOXB2 overexpression","pmids":["35315492"],"confidence":"Medium","gaps":["Single lab","Does not connect HOXB2-driven CCT6A to a specific downstream effector mechanism"]},{"year":2023,"claim":"Linked CCT6A to TGF-β/Smad/c-Myc pathway activation and EMT in esophageal carcinoma, extending the TGF-β connection to a new tumor type.","evidence":"siRNA knockdown/overexpression with TGF-β rescue and Western blot for p-Smad2/3 and c-Myc in ESCC cells","pmids":["37017854"],"confidence":"Low","gaps":["Pathway activation inferred from downstream markers without direct binding evidence","Apparent contrast with SMAD2-inhibitory model not reconciled"]},{"year":2024,"claim":"Expanded CCT6A's interactome to STAT1 and p53, showing it stabilizes STAT1 to drive HK2-dependent glycolysis and binds both wild-type and mutant p53 to regulate survivin.","evidence":"Co-IP, ChIP, transcriptomics and LC-MS in lung adenocarcinoma; Co-IP and p53-status-dependent functional readouts in colon cancer","pmids":["38750462","38997438"],"confidence":"Medium","gaps":["Mechanism by which CCT6A shields STAT1 from ubiquitination not defined","No structural basis for distinct wild-type vs mutant p53 handling"]},{"year":2024,"claim":"Connected CCT6A to glycolysis and metastasis through additional partners (TCAB1/TERT axis, RPS3), broadening its metabolic-rewiring role across tumor types.","evidence":"Co-IP and HK2 promoter assays with xenografts in cervical cancer; Co-IP and migration/invasion assays in HCC","pmids":["38657573","39630318"],"confidence":"Low","gaps":["RPS3 link rests on a single Co-IP with unresolved mechanism","Whether these converge on a common glycolytic program is untested"]},{"year":2025,"claim":"Identified TRIM38 as the E3 ligase that directly ubiquitinates CCT6A at K127/K138 for proteasomal degradation, providing the first defined mechanism controlling CCT6A protein turnover and its downstream c-Myc stabilization.","evidence":"Co-IP, ubiquitination assays, K127/K138 mutagenesis, and in vivo tumor suppression in colorectal cancer","pmids":["40047371"],"confidence":"High","gaps":["Signals that activate TRIM38-mediated CCT6A degradation unknown","Mechanism by which CCT6A stabilizes c-Myc not defined"]},{"year":2025,"claim":"Established CCT6A as an exosome-transferable factor that acts cell-non-autonomously, binding β-catenin to drive nuclear translocation and shuttling chemokines to reprogram the tumor microenvironment.","evidence":"CAF–cancer cell co-culture and exosomal transfer, Co-IP for β-catenin and chemokine interactions, nuclear fractionation, and in vivo macrophage polarization assays","pmids":["40801472","40374617"],"confidence":"Medium","gaps":["Mechanism of CCT6A loading into exosomes unknown","Single lab for each tumor context"]},{"year":null,"claim":"How CCT6A's canonical TRiC folding function relates mechanistically to its many moonlighting protein-binding and secreted activities remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural account of how a chaperonin subunit engages SMAD2, STAT1, p53, and β-catenin","Whether moonlighting functions require free CCT6A versus assembled TRiC is untested","Mechanism directing CCT6A secretion into exosomes is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7]}],"complexes":["TRiC/CCT chaperonin"],"partners":["SMAD2","STAT1","TP53","TRIM38","CTNNB1","RPS3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P40227","full_name":"T-complex protein 1 subunit zeta","aliases":["Acute morphine dependence-related protein 2","CCT-zeta-1","Chaperonin containing T-complex polypeptide 1 subunit 6A","HTR3","Tcp20"],"length_aa":531,"mass_kda":58.0,"function":"Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis (PubMed:25467444, PubMed:36493755, PubMed:35449234, PubMed:37193829). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P40227/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT6A","classification":"Common 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CCT5","url":"https://www.omim.org/entry/610150"},{"mim_id":"104613","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 6A; CCT6A","url":"https://www.omim.org/entry/104613"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCT6A"},"hgnc":{"alias_symbol":["TTCP20","TCPZ","Cctz","HTR3","TCP20"],"prev_symbol":["CCT6"]},"alphafold":{"accession":"P40227","domains":[{"cath_id":"1.10.560.10","chopping":"2-139_406-522","consensus_level":"medium","plddt":91.336,"start":2,"end":522},{"cath_id":"3.50.7.10","chopping":"209-368","consensus_level":"medium","plddt":89.3153,"start":209,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40227","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40227-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40227-F1-predicted_aligned_error_v6.png","plddt_mean":89.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT6A","jax_strain_url":"https://www.jax.org/strain/search?query=CCT6A"},"sequence":{"accession":"P40227","fasta_url":"https://rest.uniprot.org/uniprotkb/P40227.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40227/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40227"}},"corpus_meta":[{"pmid":"28375158","id":"PMC_28375158","title":"CCT6A 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Cancer.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40801472","citation_count":8,"is_preprint":false},{"pmid":"38657573","id":"PMC_38657573","title":"CCT6A Regulates Cervical Cancer Cell Glycolysis and Proliferation under Hypoxic Conditions via the Telomerase Cajal Body Protein 1/Telomerase Reverse Tranase.","date":"2024","source":"Gynecologic and obstetric investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38657573","citation_count":5,"is_preprint":false},{"pmid":"25498563","id":"PMC_25498563","title":"Immunological consequences of stress-related proteins--cytosolic tryparedoxin peroxidase and chaperonin TCP20--identified in splenic amastigotes of Leishmania donovani as Th1 stimulatory, in experimental visceral leishmaniasis.","date":"2014","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25498563","citation_count":5,"is_preprint":false},{"pmid":"39630318","id":"PMC_39630318","title":"Serine related gene CCT6A promotes metastasis of hepatocellular carcinoma via interacting with RPS3.","date":"2024","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39630318","citation_count":4,"is_preprint":false},{"pmid":"39440061","id":"PMC_39440061","title":"CCT6A functions as promising diagnostic biomarker and promotes cell proliferation in colorectal cancer.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39440061","citation_count":3,"is_preprint":false},{"pmid":"10810232","id":"PMC_10810232","title":"Cloning of rabbit Cct6 and the distribution of the Cct complex in mammalian tissues.","date":"2000","source":"Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/10810232","citation_count":2,"is_preprint":false},{"pmid":"32908372","id":"PMC_32908372","title":"Identification and Genetic Effect of Haplotypes in the Distal Promoter Region of Chicken CCT6A Gene Associated with Egg Production Traits.","date":"2016","source":"The journal of poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/32908372","citation_count":2,"is_preprint":false},{"pmid":"41399140","id":"PMC_41399140","title":"CCT6A Promotes Colon Cancer Cell Proliferation, Migration, and Invasion by Modulating Fatty Acid Metabolism and Activating the TGF-β1/Smad Signaling Pathway.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41399140","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15441,"output_tokens":3652,"usd":0.050551,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11364,"output_tokens":3616,"usd":0.07361,"stage2_stop_reason":"end_turn"},"total_usd":0.124161,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"CCT6A (Tcp20) is a subunit of the eukaryotic TRiC (TCP ring complex) chaperonin hetero-oligomeric complex, as demonstrated by gel filtration followed by Western analysis of purified bovine testis TRiC with a Tcp20-specific antibody. Gene disruption in yeast showed TCP20 is an essential gene, consistent with TRiC being required for folding of key proteins.\",\n      \"method\": \"Gel filtration + Western blotting of purified bovine TRiC; yeast gene disruption\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical isolation of the complex from purified protein, combined with genetic essentiality demonstrated by gene disruption\",\n      \"pmids\": [\"8034610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CCT6A protein is widely expressed across mammalian tissues (kidney, liver, testes, lymphocytes, reticulocytes, cultured cell lines) and the ATP-binding sites are perfectly conserved among mammals and yeast, supporting a role in ATP-dependent protein folding.\",\n      \"method\": \"Western blotting with polyclonal anti-human CCT6 antibody; cDNA cloning and sequence analysis\",\n      \"journal\": \"Experimental nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct protein detection across tissues by Western blot combined with sequence conservation analysis, single lab\",\n      \"pmids\": [\"10810232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Progesterone activates CCT6A transcription in chicken granulosa cells via a progesterone response element (PRE) located in the distal promoter (−2056 to −2051), while FSH inhibits CCT6A mRNA expression; identified by promoter deletion and mutant constructs.\",\n      \"method\": \"Promoter deletion constructs, site-directed mutagenesis, reporter assays in granulosa cells\",\n      \"journal\": \"General and comparative endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection with deletion and mutation analysis, single lab\",\n      \"pmids\": [\"23644154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCT6A directly binds SMAD2 protein and acts as an inhibitor of SMAD2 function in non-small-cell lung carcinoma (NSCLC) cells. CCT6A-mediated suppression of SMAD2 (with SMAD3 intact) switches TGF-β-induced transcriptional responses toward a prometastatic state and promotes metastasis.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), NSCLC cell lines, animal metastasis models, clinical specimens; selective SMAD3/CCT6A inhibition experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for direct binding, functional rescue in cell lines and animal models, corroborated with clinical specimens\",\n      \"pmids\": [\"28375158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB2 transcription factor directly binds the CCT6A promoter and upregulates CCT6A expression in colon cancer cells, placing HOXB2 upstream of CCT6A in a transcriptional regulatory axis that controls colon cancer proliferation, migration, and invasion.\",\n      \"method\": \"Luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), CCT6A knockdown and HOXB2 overexpression cell lines\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP and luciferase reporter confirm direct promoter binding, functional rescue experiment, single lab\",\n      \"pmids\": [\"35315492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT6A interacts with STAT1 protein and protects it from ubiquitin-mediated degradation, thereby enhancing STAT1 stability. Stabilized STAT1 then facilitates transcription of hexokinase 2 (HK2), promoting aerobic glycolysis in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), transcriptomic sequencing, liquid chromatography-mass spectrometry, CCT6A silencing\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding, ChIP for HK2 transcriptional activation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38750462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT6A directly binds both wild-type p53 (Wtp53) and mutant p53 (Mutp53), and regulates BIRC5 (survivin) expression through distinct p53-dependent and p53-independent pathways in colon cancer cells; CCT6A inhibition reduces BIRC5 expression independently of Wtp53 levels in Wtp53 cells, whereas in Mutp53 cells it mainly depends on Mutp53 levels.\",\n      \"method\": \"Co-immunoprecipitation for direct CCT6A-p53 binding; CCT6A silencing with p53 status-dependent functional readouts in vitro and in vivo\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding shown by Co-IP, functional pathway dissection in isogenic contexts, single lab\",\n      \"pmids\": [\"38997438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 E3 ubiquitin ligase directly binds CCT6A and promotes its K48-linked ubiquitination at K127/K138 residues, leading to proteasomal degradation of CCT6A. Reduced CCT6A levels in turn diminish stabilization of c-Myc protein, suppressing the MYC pathway in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation for TRIM38-CCT6A binding; ubiquitination assays; mutagenesis of K127/K138 residues; functional tumor suppression assays in vitro and in vivo\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding by Co-IP, site-specific ubiquitination demonstrated by mutagenesis, functional rescue, in vivo validation\",\n      \"pmids\": [\"40047371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT6A secreted by cancer-associated fibroblasts (CAFs) is transferred to gastric cancer cells via exosomes, where it interacts with β-catenin, inducing β-catenin phosphorylation and nuclear translocation. This activates c-Myc-mediated transcriptional suppression of glycolysis inhibitors DDIT4 and TXNIP, enhancing stemness, chemoresistance, and glycolysis.\",\n      \"method\": \"Co-culture system of CAFs and cancer cells; exosomal transfer experiments; Co-immunoprecipitation for CCT6A–β-catenin interaction; Western blot and nuclear fractionation for β-catenin translocation; ceRNA/pseudogene regulatory circuit analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for β-catenin binding, exosomal transfer experimentally demonstrated, multiple functional readouts, single lab\",\n      \"pmids\": [\"40801472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDAC-derived exosomal CCT6A promotes M2 polarization of tumor-associated macrophages via PI3K-AKT signaling. CCT6A interacts with chemokines (CXCL1, CXCL3, CCL20, CCL5) in PDAC cells (confirmed by interactomics), and exosomal CCT6A transfers these chemokines to TAMs; silencing CCT6A abrogated tumor immunosuppression and sensitized PDAC to CD47 antibody immunotherapy in vivo.\",\n      \"method\": \"Intratumoral injection of exosomes in C57BL/6 mice; multi-omics (proteomics, interactomics); CCT6A silencing in vivo; co-culture experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — interactomics for chemokine binding, exosome delivery functionally validated in vivo, multi-omics, single lab\",\n      \"pmids\": [\"40374617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT6A interacts with RPS3 (ribosomal protein S3) in hepatocellular carcinoma cells with high metastatic potential, and this interaction may potentiate HCC metastasis by affecting metabolic processes. Gain- and loss-of-function analyses confirmed CCT6A promotes HCC migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation for CCT6A-RPS3 interaction; gain/loss-of-function migration and invasion assays\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for binding, mechanistic link to metastasis not fully resolved, single lab\",\n      \"pmids\": [\"39630318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cervical cancer cells, CCT6A silencing reduces telomerase activity by inhibiting the interaction between telomerase assembly factor TCAB1 and TERT. TERT in turn activates the HK2 gene promoter; thus CCT6A promotes glycolysis under hypoxia via the TCAB1/TERT/HK2 axis.\",\n      \"method\": \"Immunofluorescence for protein localization; co-immunoprecipitation for TCAB1-TERT interaction; CCT6A siRNA knockdown; TERT inhibition and HK2 promoter transcription assay; nude mouse xenograft model\",\n      \"journal\": \"Gynecologic and obstetric investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for TCAB1-TERT interaction, promoter transcription assay, in vivo validation, single lab\",\n      \"pmids\": [\"38657573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In esophageal squamous cell carcinoma (ESCC) cells, CCT6A promotes cell proliferation, invasion, and EMT by activating the TGF-β/Smad/c-Myc pathway; CCT6A knockdown decreased p-Smad2, p-Smad3, and c-Myc expression, while TGF-β treatment compensated for the effects of CCT6A knockdown.\",\n      \"method\": \"CCT6A siRNA knockdown and overexpression; TGF-β rescue experiment; Western blot for p-Smad2, p-Smad3, c-Myc; cell proliferation, apoptosis, and invasion assays\",\n      \"journal\": \"Irish journal of medical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation inferred from downstream marker changes and TGF-β rescue, no direct binding demonstrated between CCT6A and pathway components, single lab\",\n      \"pmids\": [\"37017854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT6A promotes colon cancer cell proliferation, migration, and invasion by increasing cleavage of latency-associated peptide (LAP)-TGF-β1 to its mature form and inducing Smad2/3 phosphorylation, as well as by modulating fatty acid synthesis.\",\n      \"method\": \"Western blot for LAP-TGF-β1 cleavage and p-Smad2/3; CCT6A knockdown/overexpression; BODIPY staining for lipid droplets; nude mouse model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanism inferred from downstream readouts without direct binding evidence between CCT6A and TGF-β1, single lab\",\n      \"pmids\": [\"41399140\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT6A is the zeta subunit of the hetero-oligomeric TRiC/CCT chaperonin complex that mediates ATP-dependent folding of cytoplasmic proteins (including actin, tubulin, and others); beyond this canonical chaperonin role, CCT6A acts as a direct binding inhibitor of SMAD2 to rewire TGF-β signaling toward prometastasis, is ubiquitinated at K127/K138 by TRIM38 for proteasomal degradation, stabilizes STAT1 from ubiquitin-mediated degradation to drive HK2-dependent glycolysis, interacts with β-catenin to promote nuclear translocation and c-Myc activation, and can be transferred via exosomes from stromal or tumor cells to modulate the tumor microenvironment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT6A (Tcp20) is the zeta subunit of the eukaryotic TRiC/CCT chaperonin, a hetero-oligomeric complex required for ATP-dependent folding of cytoplasmic proteins, and its gene is essential in yeast [#0]. It is broadly expressed across mammalian tissues with ATP-binding sites conserved from yeast to mammals, consistent with this folding role [#1]. Beyond the canonical chaperonin function, CCT6A acts in cancer as a direct protein-binding partner that rewires signaling: it binds SMAD2 and selectively inhibits SMAD2 function, switching TGF-\\u03b2-induced transcription toward a prometastatic program in non-small-cell lung carcinoma [#3], and it binds STAT1 to protect it from ubiquitin-mediated degradation, stabilizing STAT1 to drive transcription of hexokinase 2 (HK2) and aerobic glycolysis [#5]. CCT6A also directly binds both wild-type and mutant p53 to regulate BIRC5/survivin through p53-dependent and p53-independent routes [#6]. CCT6A protein levels are controlled by the E3 ligase TRIM38, which directly binds CCT6A and catalyzes K48-linked ubiquitination at K127/K138 to target it for proteasomal degradation; loss of CCT6A reduces c-Myc stabilization and suppresses the MYC pathway [#7]. CCT6A is secreted via exosomes from stromal and tumor cells, where transferred CCT6A interacts with \\u03b2-catenin to promote its nuclear translocation and c-Myc-driven transcriptional programs supporting stemness, chemoresistance, and glycolysis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that CCT6A is a bona fide subunit of the TRiC/CCT chaperonin and that the gene is essential, defining its foundational role in cytoplasmic protein folding.\",\n      \"evidence\": \"Gel filtration plus Western blotting of purified bovine testis TRiC with a Tcp20-specific antibody, and yeast TCP20 gene disruption\",\n      \"pmids\": [\"8034610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not map which client proteins depend on the CCT6A subunit specifically\", \"No structural detail on CCT6A's position within the ring\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed CCT6A is widely expressed and its ATP-binding sites are evolutionarily conserved, supporting a general role in ATP-dependent folding across mammalian tissues.\",\n      \"evidence\": \"Western blotting with anti-human CCT6 antibody across tissues; cDNA cloning and sequence analysis\",\n      \"pmids\": [\"10810232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression survey does not demonstrate tissue-specific function\", \"ATP-binding sites inferred from sequence, not measured biochemically\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified hormonal transcriptional control of CCT6A, with progesterone activating and FSH inhibiting its expression via a defined promoter element.\",\n      \"evidence\": \"Promoter deletion and site-directed mutagenesis reporter assays in chicken granulosa cells\",\n      \"pmids\": [\"23644154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in chicken granulosa cells; mammalian relevance not established\", \"Functional consequence of CCT6A induction not assayed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a non-canonical CCT6A function as a direct SMAD2 binder that selectively inhibits SMAD2 to redirect TGF-\\u03b2 signaling toward metastasis, distinguishing it from a pure folding role.\",\n      \"evidence\": \"Reciprocal Co-IP, NSCLC cell lines, animal metastasis models, and clinical specimens with selective SMAD3/CCT6A inhibition\",\n      \"pmids\": [\"28375158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how CCT6A discriminates SMAD2 from SMAD3\", \"Relationship of this moonlighting role to the TRiC complex unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CCT6A downstream of HOXB2 in a transcriptional axis driving colon cancer progression, establishing an upstream regulator of CCT6A expression.\",\n      \"evidence\": \"ChIP and luciferase reporter for direct HOXB2 promoter binding; CCT6A knockdown and HOXB2 overexpression\",\n      \"pmids\": [\"35315492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not connect HOXB2-driven CCT6A to a specific downstream effector mechanism\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CCT6A to TGF-\\u03b2/Smad/c-Myc pathway activation and EMT in esophageal carcinoma, extending the TGF-\\u03b2 connection to a new tumor type.\",\n      \"evidence\": \"siRNA knockdown/overexpression with TGF-\\u03b2 rescue and Western blot for p-Smad2/3 and c-Myc in ESCC cells\",\n      \"pmids\": [\"37017854\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway activation inferred from downstream markers without direct binding evidence\", \"Apparent contrast with SMAD2-inhibitory model not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded CCT6A's interactome to STAT1 and p53, showing it stabilizes STAT1 to drive HK2-dependent glycolysis and binds both wild-type and mutant p53 to regulate survivin.\",\n      \"evidence\": \"Co-IP, ChIP, transcriptomics and LC-MS in lung adenocarcinoma; Co-IP and p53-status-dependent functional readouts in colon cancer\",\n      \"pmids\": [\"38750462\", \"38997438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CCT6A shields STAT1 from ubiquitination not defined\", \"No structural basis for distinct wild-type vs mutant p53 handling\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CCT6A to glycolysis and metastasis through additional partners (TCAB1/TERT axis, RPS3), broadening its metabolic-rewiring role across tumor types.\",\n      \"evidence\": \"Co-IP and HK2 promoter assays with xenografts in cervical cancer; Co-IP and migration/invasion assays in HCC\",\n      \"pmids\": [\"38657573\", \"39630318\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RPS3 link rests on a single Co-IP with unresolved mechanism\", \"Whether these converge on a common glycolytic program is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified TRIM38 as the E3 ligase that directly ubiquitinates CCT6A at K127/K138 for proteasomal degradation, providing the first defined mechanism controlling CCT6A protein turnover and its downstream c-Myc stabilization.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K127/K138 mutagenesis, and in vivo tumor suppression in colorectal cancer\",\n      \"pmids\": [\"40047371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that activate TRIM38-mediated CCT6A degradation unknown\", \"Mechanism by which CCT6A stabilizes c-Myc not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CCT6A as an exosome-transferable factor that acts cell-non-autonomously, binding \\u03b2-catenin to drive nuclear translocation and shuttling chemokines to reprogram the tumor microenvironment.\",\n      \"evidence\": \"CAF\\u2013cancer cell co-culture and exosomal transfer, Co-IP for \\u03b2-catenin and chemokine interactions, nuclear fractionation, and in vivo macrophage polarization assays\",\n      \"pmids\": [\"40801472\", \"40374617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CCT6A loading into exosomes unknown\", \"Single lab for each tumor context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCT6A's canonical TRiC folding function relates mechanistically to its many moonlighting protein-binding and secreted activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural account of how a chaperonin subunit engages SMAD2, STAT1, p53, and \\u03b2-catenin\", \"Whether moonlighting functions require free CCT6A versus assembled TRiC is untested\", \"Mechanism directing CCT6A secretion into exosomes is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"TRiC/CCT chaperonin\"],\n    \"partners\": [\"SMAD2\", \"STAT1\", \"TP53\", \"TRIM38\", \"CTNNB1\", \"RPS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}