Affinage

SINHCAF

SIN3-HDAC complex-associated factor · UniProt Q9NP50

Length
221 aa
Mass
24.9 kDa
Annotated
2026-06-10
17 papers in source corpus 10 papers cited in narrative 11 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

SINHCAF (FAM60A) is a core subunit of the Sin3A-HDAC histone deacetylase corepressor complex that anchors the complex to chromatin to enforce transcriptional repression of cell-cycle and developmental target genes (PMID:22984288, PMID:28554894). It binds directly to HDAC1, and HDAC1 is required for the FAM60A-SIN3A interaction, defining SINHCAF as the bridge that tethers Sin3/HDAC to its genomic targets (PMID:42045174). Through this activity it occupies SIN3-HDAC-regulated promoters such as cyclin D1 in a cell-cycle-periodic manner, where its loss raises promoter histone acetylation, derepresses cyclin D1, and drives premature S-phase entry (PMID:22865885). In pluripotent cells SINHCAF defines a variant Sin3a-Hdac complex containing Ogt and Tet1 that occupies H3K4me3-positive promoters and is required to retain the complex on chromatin, and its loss phenocopies Sin3a depletion with extended G1 and lineage-gene deregulation (PMID:28554894). The protein directs locus-specific transcriptional outputs by partnering with sequence-specific factors—repressing HIF-2α via SP1-dependent HDAC1 recruitment (PMID:29784889)—and controls promoter DNA methylation in vivo, where mouse knockout causes embryonic lethality with visceral organ hypoplasia and aberrant promoter methylation (PMID:30070635). SINHCAF-dependent histone deacetylation is required in vivo for primordial germ cell specification through repression of the kif26ab promoter (PMID:35532311), and it links to the Hippo pathway by maintaining expression of the LATS1/2 scaffold WWC3, thereby restraining YAP1 nuclear accumulation (PMID:42045174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Established that the orphan protein FAM60A is a bona fide member of the Sin3 histone deacetylase complex, placing it within a defined chromatin-repressive machinery rather than as an uncharacterized factor.

    Evidence Quantitative affinity purification-mass spectrometry identifying Sin3 deacetylase subunits as its principal partners

    PMID:22984288

    Open questions at the time
    • Did not resolve which subunit FAM60A directly contacts within the complex
    • Did not define a chromatin-recruitment or catalytic role
  2. 2012 Medium

    Provided the first cellular phenotype, linking the Sin3/FAM60A complex to suppression of cell migration and morphology control.

    Evidence siRNA knockdown of FAM60A and of SDS3 with migration and morphology readouts

    PMID:22984288

    Open questions at the time
    • Target genes mediating the migration phenotype not identified
    • Single-lab knockdown without rescue
  3. 2012 High

    Defined a concrete chromatin mechanism by showing FAM60A drives periodic HDAC1 occupancy and deacetylation at the cyclin D1 promoter to time S-phase entry.

    Evidence siRNA knockdown with ChIP, flow cytometry, RT-PCR and western blot at the cyclin D1 locus

    PMID:22865885

    Open questions at the time
    • Mechanism of cell-cycle-dependent FAM60A regulation not resolved
    • Generality beyond cyclin D1 not established
  4. 2017 High

    Showed FAM60A defines a distinct variant Sin3a complex with Ogt and Tet1 in stem cells and is essential to retain the complex on H3K4me3 promoters, connecting it to pluripotency and lineage control.

    Evidence Tandem endogenous IP-MS, ChIP, and cell cycle analysis in embryonic stem cells

    PMID:28554894

    Open questions at the time
    • How FAM60A physically stabilizes complex-chromatin association not defined
    • Functional contribution of Ogt/Tet1 within this variant complex not dissected
  5. 2018 Medium

    Demonstrated locus-specific repression by FAM60A through partnership with a sequence-specific transcription factor, repressing HIF-2α via SP1-directed HDAC1 recruitment.

    Evidence siRNA knockdown, ChIP, reciprocal co-IP and in vitro angiogenesis assay

    PMID:29784889

    Open questions at the time
    • Single-lab finding without in vivo confirmation
    • Whether SP1 partnership generalizes to other targets unknown
  6. 2018 High

    Established the in vivo requirement for Fam60a and linked the Sin3 complex to promoter DNA methylation, showing knockout is embryonic lethal with organ hypoplasia and altered methylation.

    Evidence Mouse knockout, co-IP, genome-wide DNA methylation and expression profiling

    PMID:30070635

    Open questions at the time
    • Mechanistic link between Sin3/HDAC activity and DNA methylation changes not defined
    • Direct vs indirect methylation effects at Adhfe1 not separated
  7. 2022 High

    Placed Sinhcaf in a developmental pathway by showing its histone-deacetylase activity represses kif26ab to enable primordial germ cell specification.

    Evidence Zebrafish maternal-zygotic mutant with ChIP, histone acetylation assay and kif26ab mRNA rescue

    PMID:35532311

    Open questions at the time
    • Only partial rescue by kif26ab mRNA indicates additional targets
    • Mechanism connecting kif26ab to germ plasm aggregation not detailed
  8. 2020 Medium

    Implicated FAM60A in chemoresistance via SKP2-dependent MDR1 upregulation and caspase inhibition in lung cancer.

    Evidence siRNA/shRNA knockdown, microarray and epistasis with SKP2 in cisplatin-resistant cells

    PMID:32796403

    Open questions at the time
    • Whether SKP2 regulation is direct or Sin3/HDAC-dependent unknown
    • Single-lab study without in vivo validation
  9. 2024 Medium

    Connected FAM60A to ferroptosis protection in pancreatic cancer through regulation of ACSL1/ACSL4/GPX4 downstream of a Hippo-YY1-FAM60A axis.

    Evidence Knockdown/overexpression in vitro and in vivo with luciferase/ChIP for YY1 regulation

    PMID:38314086

    Open questions at the time
    • Whether FAM60A controls the ferroptosis enzymes via its Sin3/HDAC activity unresolved
    • Single-context cancer finding
  10. 2024 Medium

    Identified a BATF2-SINHCAF interaction modulating macrophage function during M. tuberculosis infection via TTC23 and Wnt/β-catenin signaling.

    Evidence Co-IP, knockdown and macrophage infection model with pathway inhibitors

    PMID:39672395

    Open questions at the time
    • Single co-IP with limited methodological detail
    • Direct vs indirect nature of TTC23/Wnt regulation unclear
  11. 2026 High

    Resolved the core biochemical logic by showing FAM60A binds HDAC1 directly and that HDAC1 is required for the FAM60A-SIN3A interaction, and linked FAM60A loss to YAP1 activation through WWC3 downregulation.

    Evidence IP, biochemical pulldown, CRISPR/Cas9 HDAC1 knockout, proteomics, and WWC3/YAP1 rescue experiments

    PMID:42045174

    Open questions at the time
    • Structural basis of the dual-domain RNA/DNA-binding-protein associations not defined
    • Whether WWC3 is a direct Sin3/HDAC target not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single chromatin-recruitment subunit selects among its many described target loci (cyclin D1, HIF-2α, kif26ab, WWC3, ferroptosis enzymes) across cell types remains unresolved.
  • No unifying model of target-selection or partner-transcription-factor specificity
  • No structural data on the dual-domain architecture mediating partner binding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2
Partners
BATF2HDAC1OGTSIN3ASP1TET1
Complex memberships
Sin3A-HDAC complexvariant Sin3a-Hdac complex (with OGT and TET1)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FAM60A (SINHCAF) is a subunit of the Sin3 histone deacetylase complex; quantitative proteomics identified its main biochemical partners as subunits of the Sin3 deacetylase complex, and FAM60A resides in active HDAC complexes. Quantitative proteomics (affinity purification-mass spectrometry) Molecular & cellular proteomics : MCP High 22984288
2012 FAM60A (SINHCAF) loss, or loss of another Sin3 complex component SDS3, leads to a change in cell morphology and an increase in cell migration, implicating the Sin3 complex in suppressing cell migration. Loss-of-function (siRNA knockdown) with cell migration and morphology readouts Molecular & cellular proteomics : MCP Medium 22984288
2012 FAM60A (SINHCAF) is a cell cycle-regulated protein whose expression peaks in G1 and S phases; it binds to SIN3-HDAC-regulated promoters (e.g., cyclin D1) during G1/S. FAM60A depletion increases histone acetylation at the cyclin D1 promoter, elevates cyclin D1 mRNA and protein, disrupts periodic HDAC1 association with the cyclin D1 promoter, and causes premature S phase entry. siRNA knockdown, ChIP, flow cytometry, RT-PCR, western blot The Journal of biological chemistry High 22865885
2017 Fam60a defines a variant Sin3a-Hdac complex in embryonic stem cells that also contains Ogt and Tet1; Fam60a binds H3K4me3-positive promoters together with Ogt, Tet1, and Sin3a, and is essential to maintain the complex on chromatin. Depletion of Fam60a phenocopies Sin3a loss, causing reduced proliferation, extended G1, and deregulation of lineage genes. Tandem endogenous immunoprecipitation coupled with quantitative mass spectrometry, ChIP, siRNA knockdown, cell cycle analysis The EMBO journal High 28554894
2018 SINHCAF/FAM60A specifically represses HIF-2α mRNA and protein expression via its interaction with transcription factor SP1 and recruitment of HDAC1 to the HIF-2α promoter; this control results in functional changes in in vitro angiogenesis and cell viability. siRNA knockdown, ChIP, co-immunoprecipitation, RT-PCR, western blot, in vitro angiogenesis assay The Biochemical journal Medium 29784889
2018 Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex in vivo; loss of Fam60a in mice results in embryonic lethality with hypoplasia of visceral organs and is associated with aberrant (preferentially reduced) DNA methylation at a subset of gene promoters, including the target gene Adhfe1. Mouse knockout, co-immunoprecipitation, genome-wide DNA methylation analysis, gene expression profiling eLife High 30070635
2020 FAM60A overexpression in cisplatin-resistant lung cancer cells positively regulates SKP2 expression; FAM60A upregulates MDR1 and inhibits caspase 3/8, and SKP2 knockdown reverses the cisplatin-resistance phenotype induced by FAM60A overexpression. siRNA/shRNA knockdown, microarray, RT-PCR, western blot, flow cytometry Anti-cancer drugs Medium 32796403
2022 Sinhcaf-dependent histone deacetylation is essential for primordial germ cell specification in zebrafish; Sinhcaf binds the promoter of kif26ab, and loss of Sinhcaf increases histone 3 acetylation at the kif26ab promoter, silencing its expression and causing germ plasm aggregation defects and reduced PGC abundance. Injection of kif26ab mRNA partially rescues the phenotype. Zebrafish maternal-zygotic mutant, ChIP, histone acetylation assay, mRNA rescue experiment EMBO reports High 35532311
2024 BATF2 interacts with SINHCAF to regulate macrophage function during Mycobacterium tuberculosis infection by targeting TTC23 through the Wnt/β-catenin pathway; this interaction mediates inhibition of cell proliferation, promotion of inflammatory response, and impairment of antibacterial and antigen-presenting capacity. Co-immunoprecipitation, gene knockdown, macrophage infection model, pathway inhibitor experiments International journal of biological macromolecules Medium 39672395
2024 In pancreatic ductal adenocarcinoma, FAM60A regulates three ferroptosis-related metabolic enzymes (ACSL1, ACSL4, and GPX4) to protect cells from ferroptosis; YY1 transcriptionally activates FAM60A expression, and the Hippo-YY1-FAM60A axis is suppressed under nutrient deprivation. siRNA knockdown, overexpression, in vitro and in vivo tumor models, luciferase/ChIP for YY1-FAM60A regulation Research (Washington, D.C.) Medium 38314086
2026 FAM60A binds directly to HDAC1 to recruit Sin3/HDAC complex, and CRISPR/Cas9-mediated HDAC1 knockout abolishes the FAM60A-SIN3A interaction, confirming this dependency. FAM60A also has a dual-domain architecture mediating associations with RNA- and DNA-binding proteins. Loss of FAM60A downregulates WWC3 (a LATS1/2 scaffold), causing YAP1 dephosphorylation and nuclear accumulation. Restoration of FAM60A or exogenous WWC3 reactivates Hippo signaling, normalizes cell-cycle distribution, and reverses stress resistance. Immunoprecipitation, biochemical pulldown, CRISPR/Cas9 knockout, proteomics, genomics, cell cycle analysis, rescue experiments Cell death & disease High 42045174

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Human family with sequence similarity 60 member A (FAM60A) protein: a new subunit of the Sin3 deacetylase complex. Molecular & cellular proteomics : MCP 47 22984288
2017 Fam60a defines a variant Sin3a-Hdac complex in embryonic stem cells required for self-renewal. The EMBO journal 46 28554894
2012 Family with sequence similarity 60A (FAM60A) protein is a cell cycle-fluctuating regulator of the SIN3-HDAC1 histone deacetylase complex. The Journal of biological chemistry 35 22865885
2024 A Nutrient-Deficient Microenvironment Facilitates Ferroptosis Resistance via the FAM60A-PPAR Axis in Pancreatic Ductal Adenocarcinoma. Research (Washington, D.C.) 16 38314086
2016 Fam60A plays a role for production stabilities of recombinant CHO cell lines. Biotechnology and bioengineering 15 27617904
2019 FAM60A, increased by Helicobacter pylori, promotes proliferation and suppresses apoptosis of gastric cancer cells by targeting the PI3K/AKT pathway. Biochemical and biophysical research communications 14 31727367
2020 FAM60A promotes cisplatin resistance in lung cancer cells by activating SKP2 expression. Anti-cancer drugs 12 32796403
2018 SINHCAF/FAM60A and SIN3A specifically repress HIF-2α expression. The Biochemical journal 12 29784889
2018 Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters. eLife 12 30070635
2021 Loss of FAM60A attenuates cell proliferation in glioma via suppression of PI3K/Akt/mTOR signaling pathways. Translational oncology 9 34388694
2022 Restraint of FAM60A has a cancer-inhibiting role in pancreatic carcinoma via the effects on the Akt/GSK-3β/β-catenin signaling pathway. Environmental toxicology 5 35213078
2023 FAM60A promotes osteosarcoma development and progression. Cancer medicine 4 37439040
2024 BATF2/SINHCAF regulates the quantity and function of macrophages infected with Mycobacterium Tuberculosis via regulation of TTC23 through Wnt/β-catenin pathway. International journal of biological macromolecules 3 39672395
2022 Sinhcaf-dependent histone deacetylation is essential for primordial germ cell specification. EMBO reports 3 35532311
2025 FAM60A promotes proliferation and invasion of colorectal cancer cells by regulating the Wnt/β-catenin signaling pathway. Translational cancer research 2 40104705
2021 [Research Progress of FAM60A in the Regulation of Cellular Function]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 2 34238425
2026 Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation. Cell death & disease 0 42045174

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