The potential of targeting Sin3B and its associated complexes for cancer therapy

Abstract

Sin3B serves as a scaffold for chromatin-modifying complexes that repress gene transcription to regulate distinct biological processes. Sin3B-containing complexes are critical for cell cycle withdrawal, and abrogation of Sin3B-dependent cell cycle exit impacts tumor progression. Areas covered: In this review, we discuss the biochemical characteristics of Sin3B-containing complexes and explore how these complexes regulate gene transcription. We focus on how Sin3B-containing complexes, through the association of the Rb family of proteins, repress the expression of E2F target genes during quiescence, differentiation, and senescence. Finally, we speculate on the potential benefits of the inhibition of Sin3B-containing complexes for the treatment of cancer. Expert opinion: Further identification and characterization of specific Sin3B-containing complexes provide a unique opportunity to prevent the pro-tumorigenic effects of the senescence-associated secretory phenotype, and to abrogate cancer stem cell quiescence and the associated resistance to therapy.

Keywords: Cancer stem cell; Sin3B; cellular senescence; chromatin modifiers; quiescence; senescence associated secretory phenotype.

Figure 1

Sin3 and its associated proteins. Sin3 has 6 evolutionary conserved domains: 4 paired amphipathic domains (PAH, P1–4 in figure), 1 HDAC interacting domain (HID), and 1 highly conserved region (HCR). The core complex assembles around the PAH3 and HID domain whereas transcription factors are thought to associate with the PAH1 and PAH2 domains.

Figure 2

Proposed model of Sin3B mediated gene repression during cell cycle exit. Depicted is a proposed model for Sin3B mediated repression of E2F target genes during cell cycle withdrawal. (a) Depicted is a gene locus targeted by activating E2F transcription factors during normal cell growth where the promoter has activating histone marks. The chromatin is accessible for binding of the transcription machinery. (b) During cell quiescence, Sin3B-HDAC complexes associate at the promoters of E2F target genes through the recruitment of E2F4 and the Rb family of proteins. There, Sin3B-HDAC complexes deacetylate histones to impair to accessibility of the locus. (c) During differentiation, a Sin3B-HDAC-KDM5A complex bind to intragenic regions of E2F target genes to deaceylate and demethylate histones in order to compact chromatin and repress transcription. Whether MRG15 contributes to the binding to H3K36me3 is not known.

Figure 3

The dual role of the SASP in tumor progression. Depicted is a model for the role of the SASP at distinct stages of cancer development. (a) In early preneoplastic lesions, cells that acquire oncogenes become senescent. These cells exit cell cycle and generate the SASP, which functions in an autocrine manner to enforce senescence and in a paracrine manner to promote neighboring cells to become senescent. The SASP further recruits various types of immune cells, which recognize and clear senescent cells. (b) In more developed neoplastic lesions that contain fully transformed cells, the SASP generates a pro-inflammatory environment. Fibroblasts are also involved in generating the proinflammatory SASP. This in turn increases the proliferative and invasive capacity of transformed cells.

Figure 4

Increased Sin3B expression correlates with poor prognosis in acute myeloid leukemia. Data was acquired and visualized through cbioportal from the study done by The Cancer Genome Atlas Research Network [62]. (a) Oncomine plot for Sin3B status (both exome-sequencing and RNA-sequencing) showing that Sin3B is upregulated or amplified in a small subset of patients. High Sin3B levels correlates with intermediate or poor risk disease. (b) Worse overall survival for patients with increased Sin3B expression. Curves were compared using the log-rank test.