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Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation

ABSTRACT: FAM60A, a Sin3/HDAC subunit with defined chromatin roles, has broader functions unveiled here. Integrating immunological, biochemical, CRISPR/Cas9, genomic and proteomic analyses, we mapped the FAM60A interaction network. Proteomic profiling revealed direct binding to HDAC1 and associations with RNA and DNA binding proteins. HDAC1 knockout abolished FAM60A–SIN3A complex formation. FAM60A loss rewired transcription, downregulating WWC3 scaffold levels and triggering YAP1 dephosphorylation, nuclear accumulation, G₁ enrichment and metabolic stress resistance. Reintroducing FAM60A or WWC3 restored Hippo off signaling, normalized cell-cycle distribution and reversed stress resistance. These findings position FAM60A as an epigenetic tuner of Hippo signaling via the FAM60A–HDAC1–WWC3 axis and highlight its therapeutic potential in YAP-driven cancers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dennis Province

LAB HEAD: Sayem Miah PhD

PROVIDER: PXD066554 | Pride | 2026-05-01

REPOSITORIES: Pride

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			Action	DRS
	Hs293_Txf_Halo_Fam60A_CIA_Motif_1_Ti_101.RAW	Raw
	Hs293_Txf_Halo_Fam60A_CIA_Motif_1_Ti_101.mgf	Mgf
	Hs293_Txf_Halo_Fam60A_CIA_Motif_1_Ti_101.mzid	Mzid
	Hs293_Txf_Halo_Fam60A_CIA_Motif_1_Ti_102.RAW	Raw
	Hs293_Txf_Halo_Fam60A_CIA_Motif_1_Ti_102.mgf	Mgf

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Loss of FAM60A disrupts Sin3/HDAC control of the Hippo signaling and promotes oncogenic YAP1 activation

Project description:FAM60A (also known as SINHCAF) is a subunit of the Sin3/HDAC histone deacetylase complex with established roles in chromatin remodeling, yet its broader cellular functions remain largely undefined. Using immunological, biochemical, CRISPR/Cas9, genomic, and proteomic approaches, we mapped the FAM60A interaction network and its functional impact. We reveal that FAM60A binds directly to HDAC1 to recruit Sin3/HDAC to SIN3A, while a dual domain architecture mediates additional associations with RNA and DNA binding proteins. CRISPR/Cas9–mediated HDAC1 knockout abolishes the FAM60A–SIN3A interaction, confirming this dependency. Loss of FAM60A triggers widespread transcriptional rewiring, including downregulation of WWC3—a scaffold for LATS1/2 activation. Consequently, YAP1 dephosphorylation and nuclear accumulation shifted cell-cycle dynamics toward G₁ enrichment and conferred resistance to metabolic stress. Restoration of FAM60A or exogenous WWC3 reactivated Hippo “off” signaling, normalized cell-cycle distribution, and reversed stress resistance. These findings establish FAM60A as a pivotal epigenetic tuner linking histone deacetylation to Hippo pathway regulation and nominate the FAM60A–HDAC1–WWC3 axis as a potential therapeutic target to restore growth control in YAP-driven cancers.

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SIN3A regulates porcine early embryonic development by modulating CCNB1 expression

Project description:SIN3A is the central scaffold protein of the SIN3/HDAC transcriptional repressor complex. We previously found that SIN3A participates in the mouse preimplantation development by finetuning HDAC1 expression. However, it remains unresolved if this functional significance of SIN3A was conserved in other mammals. The objective of this work was thus to characterize the expression profiles and the functional role of SIN3A in preimplantation development using non-rodent animal models. RNA-seq results show a large amount of SIN3A mRNA is present in oocytes and early embryos prior to embryonic genome activation and a low amount thereafter, suggesting a maternal origin of SIN3A in all species examined. Interestingly, immunofluorescence data show that SIN3A protein level peaks at 4-cell stage in pigs compared with morula stage in cattle, suggesting a differential role of SIN3A among species. Indeed, SIN3A depletion in early embryos causes a developmental arrest at 2-cell stage in pigs but does not affect bovine early embryonic development. In contrast with mouse data, SIN3A depletion results in only a slight decrease and even no difference in HDAC1 expression in porcine and bovine early embryos, respectively. In addition, HDAC1 knockdown does not cause 2-cell block, however, leads to a reduced blastocyst rate, suggesting the effect of SIN3A depletion on porcine early embryos is independent of HDAC1. By using un-biased RNA-seq approach, we found that CCNB1 transcript level is dramatically reduced. Moreover, CCNB1 knockdown results in a similar phenotype as SIN3A depletion. Injection of exogenous CCNB1 into SIN3A-depleted embryos could partly rescue embryonic development beyond 2-cell stage. In conclusion, our results indicate SIN3A plays an essential role in porcine early embryonic development, which probably involving the regulation of CCNB1 expression.

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Genome-wide maps of Sin3A and Sin3B binding in C2C12 myoblasts and differentiated myotubes

Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects Examination of Sin3A and Sin3B binding during myogenesis

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2025-08-22 | PXD060154 | Pride

The six unique histone deacetylase (HDAC) 1 complexes vary greatly in abundance and utilize distinct molecular assemblies.

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Transcriptome analysis upon overexpression of SIN3 187HA in Drosophila cultured cells

Project description:SIN3 is a master transcriptional scaffold protein. SIN3 interacts with RPD3 and other accessory proteins to form a histone modifying complex. A single Sin3A gene encodes multiple isoforms of SIN3, of which SIN3 187 and SIN3 220 are the predominant isoforms. Previous studies demonstrated that SIN3 isoforms play non-redundant roles during fly development. In the current study, we sought to investigate the genes regulated by SIN3 187.

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Transcriptome analysis upon SIN3 or dKDM5/LID knockdown or both under normal and paraquat induced stress conditions in Drosophila S2 cultured cells

Project description:SIN3 the scaffold protein of a histone deacetylase complex interacts with a histone demethylase KDM5 (little imaginal discs - LID) in Drosophila. Reduction of SIN3 or dKDM5/LID both result in similar phenotypes during cell proliferation and wing development. To identify underlying transcriptional changes that may contribute to these phentypic defects we performed whole genome expression analysis in Drosophila cultured cells upon RNAi-mediated knockdown of Sin3A, lid or both. We identified a large number of genes regulated by SIN3, dKDM5/LID or both. While many common genes were regulated by SIN3 and dKDM5/LID an enrichment for genes involved in stress tolerance pathways was observed. Additional RNAseq analysis of expression changes upon knockdown of Sin3A, lid or both under paraquat mediated oxidative stress conditions identified significant changes in genes involved in cell cycle related processes. Drosophila S2 cells were treated with dsRNA targetting Sin3A, lid and both or GFP as control under normal or oxidative stress conitions induced by treatment with paraquat. mRNA profiling of these samples were performed by deep sequencing using Illumina Hiseq2500.Three biological replicates were performed.

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The six unique histone deacetylase (HDAC) 1 complexes vary greatly in abundance and utilize distinct molecular assemblies

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