ABSTRACT
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. 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 tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. 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 deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
Subject(s)
DNA-Binding Proteins/genetics , Histone Deacetylases/metabolism , Mutation , Nuclear Proteins/genetics , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Acetylation , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases , Dose-Response Relationship, Drug , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Histone Deacetylase 6 , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Humans , Mice, Transgenic , Neoplasm Invasiveness , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phosphatidylinositol 3-Kinases/genetics , Promoter Regions, Genetic , Protein Processing, Post-Translational , RNA Interference , Signal Transduction , Transcription, Genetic , Transfection , Tumor Burden , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor ß (Tgf-ß) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.
