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An epigenetic mechanism underlying chromosome 17p deletion-driven tumorigenesis

ABSTRACT: Chromosome copy number variations are a hallmark of human cancers and among them chromosome 17p loss is the most common one and associated with poor prognosis. Our previous work demonstrates that 17p deletions can promote tumorigenesis more than p53 loss. Herein, with multiple functional genetic strategies, we identify a new 17p tumor suppressor, PHD finger protein 23 (PHF23). PHF23 deficiency impaires B cell differentiation and promotes Myc-driven lymphoma. Mechanistically, PHF23, a H3K4me3 reader, directly binds and represses the deacetylation activity of the SIN3-HDAC complex through its N-terminus, which coordinates two major active histone markers H3K4me3 and H3K27ac for activation of downstream B cell-differentiation genes and tumor suppressors. Further, we show that dysregulation of the PHF23-SIN3-HDAC complex is essential for PHF23 deficiency-induced tumorigenesis and maintenance. Hence, our study reveals a novel epigenetic regulatory mechanism that contributed to the pathology of 17p deleted cancers and suggests novel susceptibility of this miserable disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE145190 | GEO | 2020/12/20

REPOSITORIES: GEO

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Project description:The Sin3 histone deacetylase (HDAC) complex is a 1.2 MDa chromatin modifying complex that can repress transcription by binding to gene promoters and deacetylating histones. The Sin3/HDAC complex can affect cell cycle progression through multiple mechanisms and is among the targets of anticancer drugs, called HDAC inhibitors. We describe the identification of a new subunit of the Sin3 complex named family with sequence similarity 60 member A (FAM60A). We show that FAM60A/Sin3 complexes normally suppress the epithelial-to-mesenchymal transition (EMT) and cell migration. This occurs through transcriptional repression of genes that encode components of the TGF-beta signaling pathway. This work reveals that FAM60A and the Sin3 complex are upstream repressors of TGF-beta signaling, EMT and cell migration and extends the known biological roles of the Sin3 complex. This experiment investigates the role of FAM60A in gene expression by comparing A549 lung cancer cells treated with or without siRNA against FAM60A. The Sin3 histone deacetylase (HDAC) complex is a 1.2 MDa chromatin modifying complex that can repress transcription by binding to gene promoters and deacetylating histones. SDS3 is a core component of the Sin3 complex. The Sin3/HDAC complex can affect cell cycle progression through multiple mechanisms and is among the targets of anticancer drugs, called HDAC inhibitors. We describe the identification of a new subunit of the Sin3 complex named family with sequence similarity 60 member A (FAM60A). We show that FAM60A/Sin3 complexes normally suppress the epithelial-to-mesenchymal transition (EMT) and cell migration. This occurs through transcriptional repression of genes that encode components of the TGF-beta signaling pathway. This work reveals that FAM60A and the Sin3 complex are upstream repressors of TGF-beta signaling, EMT and cell migration and extends the known biological roles of the Sin3 complex. As a base line to better understand the relationship between FAM60A and the Sin3 complex, this experiment investigates the gene expression changes which occur in A549 lung cancer cells when the Sin3 complex is perturbed by knockdown of a core component via siRNA against SDS3. FAM60A siRNA knockdowns were compared to a non-targeting control in triplicate, for a total of 6 samples. SDS3 siRNA knockdowns were compared to a non-targeting control in triplicate, for a total of 6 samples.

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An epigenetic mechanism underlying chromosome 17p deletion-driven tumorigenesis

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