ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers.   ARID1A and TP53 mutations are typically mutually exclusive.  Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers.  Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors.  This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors.  The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A.  HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells.  HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification.   Thus, ARID1A mutation inactivates p53 apoptotic function by upregulating HDAC6.  These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation SOURCE: Priyankara,J,Wickramasinghe (priyaw@wistar.org) - Lieberman The Wistar Institute

Pluto Bioinformatics

GSE84405: ARID1A-mutated ovarian cancers depend on HDAC6 activity