Affinage

NCOA5

Nuclear receptor coactivator 5 · UniProt Q9HCD5

Length
579 aa
Mass
65.5 kDa
Annotated
2026-06-10
23 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCOA5 is a nuclear receptor coregulator that gates inflammatory and metabolic gene programs and, through them, suppresses tumorigenesis in a tissue- and sex-dependent manner (PMID:24332041, PMID:25755249). Its best-defined activity is transcriptional repression of IL-6: heterozygous loss of Ncoa5 in mice elevates IL-6 and drives male-specific spontaneous hepatocellular carcinoma preceded by glucose intolerance and hepatic steatosis, with IL-6 blockade averting these phenotypes and placing NCOA5 genetically upstream of IL-6 (PMID:24332041), and the same NCOA5→IL-6 axis governs epididymal epithelial function and sperm maturation (PMID:31664153). NCOA5 also acts as an LXR corepressor, being recruited to the Abca1 promoter upon TLR3 signaling to displace RNA polymerase II and reduce macrophage cholesterol efflux, thereby coupling pro- and anti-inflammatory programs (PMID:25755249). The protumorigenic liver microenvironment caused by NCOA5 deficiency operates through downstream p21WAF1/CIP1 overexpression (PMID:32203160), and myeloid-lineage-specific deletion alone is sufficient to cause NASH and HCC via macrophage PF4 overexpression that induces hepatocyte lipogenesis (PMID:37734594). In cancer cells NCOA5 has context-dependent roles: it can suppress HCC proliferation by inducing G2/M arrest, DNA damage, and senescence, an activity lost by the T445A substitution (PMID:28137631), yet in other settings it promotes proliferation, migration, and EMT and sustains tumor growth (PMID:29296214, PMID:29626478). Additional reported activities include direct binding of the mTOR promoter to activate mTOR signaling downstream of PI3K (PMID:32736675), inhibition of ferroptosis via a MYC–GPX4 axis (PMID:40316542), and repression of PRDX6 through interference with NRF2-mediated transactivation (PMID:40619029).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 High

    Established NCOA5 as a tumor suppressor in liver and defined IL-6 as its key downstream effector, answering whether NCOA5 dosage causally controls a carcinogenic inflammatory program.

    Evidence Ncoa5+/- haploinsufficient mice with IL-6 blockade rescue and genetic epistasis

    PMID:24332041

    Open questions at the time
    • Molecular mechanism by which NCOA5 represses IL-6 transcription not resolved
    • Basis of the strict male specificity of HCC not explained
    • Direct DNA/receptor binding events at IL-6 locus not shown
  2. 2015 High

    Defined a direct biochemical mechanism for NCOA5 as an LXR corepressor recruited to a target promoter, showing how it links inflammatory signaling to lipid metabolism.

    Evidence Promoter enrichment-quantitative mass spectrometry, ChIP, cholesterol efflux assay in macrophages with TLR3 stimulation

    PMID:25755249

    Open questions at the time
    • Whether NCOA5 acts as corepressor at other LXR targets unknown
    • Structural basis of NCOA5-LXR interaction not determined
    • Relationship between corepressor activity and IL-6 repression not connected
  3. 2017 Medium

    Tested NCOA5's role within cancer cells directly, revealing context-dependent functions ranging from growth suppression to growth promotion.

    Evidence Tet-On NCOA5wt vs T445A in HCC cells with xenografts (cell cycle/DNA damage/senescence readouts); separately, knockdown/overexpression in CRC cells with PI3K inhibitor rescue

    PMID:28137631 PMID:29296214

    Open questions at the time
    • Opposing pro- and anti-tumorigenic roles not reconciled mechanistically
    • Functional importance of the T445 residue at the molecular level unknown
    • Single-lab cell-line studies without cross-validation
  4. 2018 Medium

    Confirmed NCOA5 supports HCC malignant phenotypes including EMT via clean genetic ablation, complementing dosage models.

    Evidence CRISPR/Cas9 NCOA5 knockout in HCC cell lines with proliferation, microsphere, migration, and EMT marker assays

    PMID:29626478

    Open questions at the time
    • Transcriptional targets driving EMT not identified
    • Apparent contradiction with growth-suppressive role in same tissue unresolved
  5. 2019 High

    Generalized the NCOA5→IL-6 axis beyond liver, showing it controls a distinct physiological process (sperm maturation) through the same effector.

    Evidence Ncoa5+/- mice with Il-6 heterozygous deletion rescue and IL-6 IHC in epididymis

    PMID:31664153

    Open questions at the time
    • Mechanism of IL-6 repression in epididymal epithelium not defined
    • Cell-autonomous vs systemic contribution not separated
  6. 2020 High

    Placed p21WAF1/CIP1 downstream of NCOA5 in building the protumorigenic liver niche, extending the pathway beyond IL-6.

    Evidence Ncoa5+/- ; p21+/- double-mutant genetic rescue with transcriptomics and metformin intervention

    PMID:32203160

    Open questions at the time
    • Whether p21 induction is direct or downstream of IL-6 not resolved
    • Cell type responsible for p21 overexpression not pinpointed
  7. 2020 Medium

    Introduced a direct transcriptional-activation function, showing NCOA5 binds the mTOR promoter to relay PI3K signaling, broadening its mechanistic repertoire beyond corepression.

    Evidence ChIP-qPCR, gain/loss-of-function, and PI3K inhibition in bovine mammary epithelial cells

    PMID:32736675

    Open questions at the time
    • Whether NCOA5 binds the mTOR promoter in human/mammalian cancer cells unknown
    • Coactivator/corepressor cofactors at the mTOR promoter not identified
    • Single-lab study in a non-mammalian-cancer system
  8. 2023 High

    Demonstrated cell-type-specific sufficiency, proving myeloid NCOA5 loss alone drives NASH/HCC through macrophage PF4-mediated hepatocyte lipogenesis.

    Evidence Myeloid-specific conditional Ncoa5 knockout mice with macrophage transcriptomics and PF4 functional studies

    PMID:37734594

    Open questions at the time
    • How NCOA5 represses PF4 transcription in macrophages not defined
    • Relationship between PF4 axis and the earlier IL-6 axis not integrated
  9. 2025 Medium

    Linked NCOA5 to redox/cell-death control, identifying ferroptosis inhibition via MYC-GPX4 and PRDX6 repression via NRF2 interference as additional effector pathways.

    Evidence Knockdown/overexpression with rescue (GPX4 or PRDX6) and in vivo validation in sorafenib-resistant HCC and NSCLC cells

    PMID:40316542 PMID:40619029

    Open questions at the time
    • Whether NCOA5 regulates MYC and NRF2 targets directly or indirectly unclear
    • Single-lab studies for each axis without independent replication
    • Connection between these redox roles and the IL-6/tumor-suppressor model unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single coregulator switches between corepressor (IL-6, Abca1/LXR, PRDX6/NRF2) and activator (mTOR, GPX4) functions, and what determines its tissue- and sex-specific tumor-suppressive versus tumor-promoting outputs, remains unresolved.
  • No structural model or defined recruitment logic for NCOA5 at target promoters
  • Determinants of context-dependent pro- vs anti-tumor activity unknown
  • Mechanistic basis of male-specific phenotypes unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
LXRTPX2

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Heterozygous deletion of Ncoa5 in mice causes spontaneous HCC exclusively in males, preceded by increased IL-6 expression, early-onset glucose intolerance, and progressive hepatic steatosis and dysplasia; blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development, placing NCOA5 upstream of IL-6 in this pathway. Ncoa5+/- mouse model (haploinsufficiency), IL-6 blockade experiment, genetic epistasis Cancer cell High 24332041
2015 NCOA5 functions as an LXR corepressor at the Abca1 promoter in macrophages; TLR3 signaling promotes recruitment of NCOA5 to the Abca1 promoter together with loss of RNA polymerase II, resulting in reduced cholesterol efflux, thereby mediating crosstalk between pro-inflammatory and anti-inflammatory pathways. Promoter enrichment-quantitative mass spectrometry (PE-QMS), ChIP, loss-of-function experiments, cholesterol efflux assay The EMBO journal High 25755249
2019 Heterozygous deletion of Ncoa5 in mice leads to increased IL-6 expression in epididymal epithelial cells, causing decreased sperm motility and male infertility; heterozygous deletion of Il-6 in Ncoa5+/- mice partially rescued spermatozoa motility and infertility, establishing NCOA5 as an upstream regulator of IL-6 in epididymal sperm maturation. Ncoa5+/- mouse model, immunohistochemistry for IL-6, genetic rescue by Il-6 heterozygous deletion Scientific reports High 31664153
2020 NCOA5 deficiency in mice leads to p21WAF1/CIP1 overexpression in liver; heterozygous deletion of p21WAF1/CIP1 in Ncoa5+/- mice alleviated key features of the protumorigenic niche, placing p21WAF1/CIP1 downstream of NCOA5 in the development of the HCC-associated liver microenvironment. Ncoa5+/- mouse model, p21WAF1/CIP1 heterozygous deletion genetic rescue, transcriptomic analysis, metformin pharmacological intervention Oncogene High 32203160
2023 Myeloid-lineage-specific deletion of Ncoa5 is sufficient to cause spontaneous NASH and HCC in male mice; NCOA5-deficient intrahepatic macrophages overexpress PF4, which triggers lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression, establishing a NCOA5-PF4 axis in macrophages as a driver of NAFLD/NASH. Myeloid-lineage-specific Ncoa5 conditional knockout mice, transcriptomic analysis of intrahepatic macrophages, in vitro and in vivo PF4 functional studies Cellular and molecular gastroenterology and hepatology High 37734594
2017 NCOA5 promotes colorectal cancer cell proliferation, migration, and invasion by upregulating p-AKT, Cyclin D1, and MMP9 while downregulating P27 via the PI3K/AKT signaling pathway; PI3K inhibitor LY294002 blocked these NCOA5-mediated effects, and knockdown of Cyclin D1 or MMP9 blocked the tumor-promoting activity of NCOA5. NCOA5 knockdown/overexpression in CRC cell lines, PI3K inhibitor rescue, xenograft tumor model, western blotting for pathway components Oncotarget Medium 29296214
2017 Wild-type NCOA5 suppresses HCC cell proliferation via induction of G2/M arrest and increases DNA damage and cell senescence; the T445A amino acid substitution (Thr to Ala) significantly impairs these activities, as shown by reduced G2/M arrest, decreased DNA damage/senescence induction, and loss of tumor growth inhibitory function in xenograft models. Tet-On inducible expression of NCOA5wt vs NCOA5T445A in HCC cells, xenograft tumor model, cell cycle analysis, DNA damage and senescence assays Cancer letters Medium 28137631
2018 CRISPR/Cas9-mediated knockout of NCOA5 in HCC cells inhibits proliferation, tumor microsphere formation, migration, and suppresses epithelial-mesenchymal transition (EMT). CRISPR/Cas9 NCOA5 knockout in HCC cell lines, proliferation assay, tumor microsphere formation, migration assay, EMT marker analysis Biochemical and biophysical research communications Medium 29626478
2020 In bovine mammary epithelial cells, NCOA5 binds directly to the mTOR promoter (confirmed by ChIP-qPCR); NCOA5 overexpression increases mTOR phosphorylation and β-casein synthesis, while knockdown has opposite effects; PI3K inhibition abolishes amino acid-induced NCOA5 upregulation, placing NCOA5 downstream of PI3K and upstream of mTOR in amino acid signaling. ChIP-qPCR (NCOA5 binding to mTOR promoter), NCOA5 overexpression/knockdown, PI3K inhibition, measurement of mTOR phosphorylation and β-casein synthesis Biochemical and biophysical research communications Medium 32736675
2025 NCOA5 inhibits ferroptosis in HCC cells by maintaining GPX4 levels via the transcription factor MYC; NCOA5 knockdown decreases GPX4 expression, sensitizes sorafenib-resistant HCC cells to sorafenib, and induces ferroptosis; overexpression of GPX4 rescues the ferroptosis induced by NCOA5 knockdown. NCOA5 knockdown in sorafenib-resistant HCC cell lines, GPX4 expression analysis, MYC transcription factor studies, in vivo xenograft validation, rescue by GPX4 overexpression Cell death discovery Medium 40316542
2025 NCOA5 represses PRDX6 expression by interfering with NRF2-mediated transactivation; loss of PRDX6 phenocopies NCOA5 overexpression (increased ROS, increased cisplatin sensitivity), and enforced PRDX6 expression reverses the effects of NCOA5 on ROS production and cisplatin sensitivity in NSCLC cells. NCOA5 overexpression/knockdown in NSCLC cells, PRDX6 expression analysis, ROS measurement, NRF2-mediated transactivation assay, rescue by PRDX6 overexpression, in vivo validation Biochemical pharmacology Medium 40619029
2013 An ortholog of NCOA5 is essential for maintenance of the pluripotent stem cell population in planarians; NCOA5 was identified as enriched in planarian stem cells by in vivo SILAC proteomics comparing normal vs. stem cell-depleted planarians. In vivo SILAC proteomics in planarians, stem cell depletion comparison, functional knockdown of Ncoa5 in planarians Cell reports Low 24268775
2023 TPX2 interacts with NCOA5 (confirmed by co-immunoprecipitation); NCOA5 acts as a downstream target of TPX2 in promoting proliferation, migration, invasion, and angiogenesis in breast cancer cells, as NCOA5 overexpression reversed the suppressive effects of TPX2 knockdown. Co-immunoprecipitation (TPX2–NCOA5 interaction), NCOA5/TPX2 knockdown and overexpression in breast cancer cell lines, rescue epistasis experiment Experimental and therapeutic medicine Low 37229326

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma. Cancer cell 58 24332041
2013 SILAC proteomics of planarians identifies Ncoa5 as a conserved component of pluripotent stem cells. Cell reports 39 24268775
2017 NCOA5 promotes proliferation, migration and invasion of colorectal cancer cells via activation of PI3K/AKT pathway. Oncotarget 33 29296214
2015 An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux. The EMBO journal 31 25755249
2014 NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell metabolism 23 24411937
2018 Knockout of NCOA5 impairs proliferation and migration of hepatocellular carcinoma cells by suppressing epithelial-to-mesenchymal transition. Biochemical and biophysical research communications 20 29626478
2020 NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which is reversed by metformin. Oncogene 19 32203160
2014 NCOA5 low expression correlates with survival in esophageal squamous cell carcinoma. Medical oncology (Northwood, London, England) 15 25416054
2011 A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a Southern European population: a case-control study. Human immunology 15 21645569
2020 NCOA5 is a master regulator of amino acid-induced mTOR activation and β-casein synthesis in bovine mammary epithelial cells. Biochemical and biophysical research communications 11 32736675
2014 NCOA5, a molecular link between type 2 diabetes and liver cancer. Hepatobiliary surgery and nutrition 11 25019069
2019 NCOA5 Haplo-insufficiency Results in Male Mouse Infertility through Increased IL-6 Expression in the Epididymis. Scientific reports 10 31664153
2018 A novel tumor suppressor gene NCOA5 is correlated with progression in papillary thyroid carcinoma. OncoTargets and therapy 8 29391807
2023 NCOA5 Haploinsufficiency in Myeloid-Lineage Cells Sufficiently Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. Cellular and molecular gastroenterology and hepatology 7 37734594
2017 A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation. Cancer letters 7 28137631
2021 Knockdown of NCOA5 suppresses viability, migration and epithelial-mesenchymal transition, and induces adhesion of breast cancer cells. Oncology letters 6 34457049
2017 Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet's disease. EXCLI journal 6 28694762
2023 Expression and clinical significance of NCOA5 in epithelial ovarian cancer. Frontiers in oncology 3 37197435
2023 Role of the TPX2/NCOA5 axis in regulating proliferation, migration, invasion and angiogenesis of breast cancer cells. Experimental and therapeutic medicine 3 37229326
2025 NCOA5 induces sorafenib resistance in hepatocellular carcinoma by inhibiting ferroptosis. Cell death discovery 2 40316542
2021 Analysis of Nuclear Receptor Coactivator 5 (NCOA5) Messenger RNA Expression and rs2903908 Single Nucleotide Polymorphism of NCOA5 in an Egyptian Cohort with Behçet's Disease: A Single-Center Case-control Study. Ocular immunology and inflammation 1 34255592
2025 NCOA5 suppresses tumor progression and cisplatin resistance in non-small cell lung cancer by interfering with PRDX6 transcription. Biochemical pharmacology 0 40619029
2023 Could NCOA5 a novel candidate gene for multiple sclerosis susceptibility? Molecular biology reports 0 37817021

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