Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes

Abstract

SynopsisThe multiprotein SWI-independent 3 (Sin3)-HDAC (histone deacetylase) corepressor complex mediates gene repression through its interaction with DNA-binding factors and recruitment of chromatin-modifying proteins on to the promoters of target gene. Previously, an increased expression of Sin3B and tumour suppressor protein, p53 has been established upon adriamycin treatment. We, now provide evidence that Sin3B expression is significantly up-regulated under variety of stress conditions and this response is not stress-type specific. We observed that Sin3B expression is significantly up-regulated both at transcript and at protein level upon DNA damage induced by bleomycin drug, a radiomimetic agent. This increase in Sin3B expression upon stress is found to be p53-dependent and is associated with enhanced interaction of Sin3B with Ser 15 phosphorylated p53. Binding of Sin3-HDAC repressor complex on to the promoters of p53 target genes influences gene regulation by altering histone modifications (H3K9me3 and H3K27me3) at target genes. Furthermore, knockdown of Sin3B by shRNA severely compromises p53-mediated gene repression under stress conditions. Taken together, these results suggest that stress-induced Sin3B activation is p53-dependent and is essential for p53-mediated repression of its selective target genes. The present study has an implication in understanding the transrepression mechanism of p53 under DNA damaging conditions.

Emerging Roles of Epigenetic Regulator Sin3 in Cancer

“…The impact of this biological response on tumorigenesis has been studied in detail (Rielland et al, 2014) and elaborated in Section 7. Similarly, levels of both Sin3A and Sin3B increase under conditions of genotoxic stress and have been shown to be important for increasing stability and trans-repressive functions of tumor suppressor TP53 (Bansal et al, 2011;Kadamb, Mittal, Bansal, & Saluja, 2015;Murphy et al, 1999;Zilfou, Hoffman, Sank, George, & Murphy, 2001). Sin3 proteins also interact with retinoblastoma family of tumor suppressors via RBP1 member of the Sin3 complex for repressing transcription of E2F-responsive pro-proliferative genes (Lai et al, 2001).…”

Soft repression: Subtle transcriptional regulation with global impact

“…SIN3 also regulates response to stress in both fly and mammalian models. [ 40,42 ] The knockdown of Sin3A in Drosophila leads to reduction in expression of genes encoding proteins required for glutathione synthesis as well as increased susceptibility to oxidative stress, a sensitivity that is rescued by glutathione supplementation. [ 40 ] A study in mammalian cancer cell lines showed that SIN3B is important in the stress response to treatment with different DNA‐damaging agents.…”

“…[ 40 ] A study in mammalian cancer cell lines showed that SIN3B is important in the stress response to treatment with different DNA‐damaging agents. [ 42 ] Following treatment, there is an increase in expression of SIN3B at the transcript and protein level, which is p53‐dependent. Additionally, when Sin3B is knocked down during damage, p53 target stress response genes are affected, linking SIN3B to the p53‐mediated response to DNA damage.…”

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

“…SIN3 interacts with Class I histone deacetylases (HDAC1/2) and accessory proteins forming the SIN3/HDAC chromatin modifying complex [8] . Transcription factors that specifically bind to one or more of the four paired amphipathic helical (PAH1–4) domains of SIN3A provide interface for assembly of multiple proteins [ 9 , 10 ]. These proteins bind to SIN3 via their amino acid sequence specific SIN3-interaction domain (SID) and are known as SID proteins.…”