Abstract 3838: HDAC5-mediated deacetylation promotes SATB1 oncogenic functions

Abstract

Abstract HDAC5, a class IIa histone deacetylase is a prominent transcriptional regulator. The functions of HDAC5 have been shown to be regulated via phosphorylation-dependent nuclear-cytoplasmic shuttling. Phosphorylation of two conserved Ser259 and Ser498 residues by calcium/calmodulin dependent protein kinase promotes HDAC5 nuclear export. Dysregulation of HDAC5 has been implicated in development of many pathogenic conditions including cardiac hypertrophy and cancer. However, the mechanisms underlying the role of HDAC5 in tumorigenesis are not well understood. In order to explore the role of HDAC5 in tumorigenesis, we performed a proteomic screen and identified several interacting proteins of HDAC5. In vitro and in vivo studies further confirmed SATB1 as a novel interacting partner of HDAC5. SATB1 (Special AT rich binding protein 1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate several genes. It has been recently reported to be overexpressed in various cancers and associated with malignant behavior of cancer cells. Our studies revealed SATB1 as a novel substrate of HDAC5-mediated deacetylation during early phase of genotoxic stress. We also mapped the site of deacetylation to the highly conserved K411 residue of SATB1. Upon prolonged genotoxic stress when HDAC5 undergoes nuclear export, SATB1 acetylation was observed. Thus, we screened a shRNA library targeting nuclear histone acetyltransferases and identified Tip60 as the cognate histone acetyltransferase involved in SATB1 acetylation at K411 residue. Next we performed qPCR array and found SATB1 upregulates the expression of genes involved in tumor suppression in acetylation-dependent manner. Increased SATB1 acetylation leads to decreased cell proliferation capacity, migration and invasiveness of tumor cells. Furthermore, studies in mouse tumor models confirmed that HDAC5 promotes SATB1-mediated tumorigenesis. Taken together, our findings add to the substrate repertoire of HDAC5 and provides key insights into SATB1-mediated tumorigenesis. Citation Format: Shalakha Sharma, Dr. Sanjeev Das. HDAC5-mediated deacetylation promotes SATB1 oncogenic functions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3838.