ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

• Published in: Nature genetics Vol. 52; no. 2; pp. 187 - 197
• Main Authors: Nagarajan, Sankari, Rao, Shalini V., Sutton, Joseph, Cheeseman, Danya, Dunn, Shanade, Papachristou, Evangelia K., Prada, Jose-Enrique Gonzalez, Couturier, Dominique-Laurent, Kumar, Sanjeev, Kishore, Kamal, Chilamakuri, Chandra Sekhar Reddy, Glont, Silvia-Elena, Archer Goode, Emily, Brodie, Cara, Guppy, Naomi, Natrajan, Rachael, Bruna, Alejandra, Caldas, Carlos, Russell, Alasdair, Siersbæk, Rasmus, Yusa, Kosuke, Chernukhin, Igor, Carroll, Jason S.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2020; Nature Publishing Group
• Subjects: 45/15; 45/47; 631/337/2019; 631/67/1347; Acetylation; Agriculture; Animal Genetics and Genomics; Animals; Binding sites; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Cancer Research; Cancer therapies; Care and treatment; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation; Chromatin; Clonal deletion; Cloning; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Domains; Drug resistance; Drug Resistance, Neoplasm - genetics; Estrogen; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Forkhead protein; Fulvestrant; Gene deletion; Gene Expression Regulation, Neoplastic; Gene Function; Genes; Genomes; Genomics; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - metabolism; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Human Genetics; Humans; Lysine; MCF-7 Cells; Medical research; Medicine, Experimental; Mice, Inbred NOD; Mutation; Proteins; Recruitment; Regulatory sequences; Sensitizing; SWI/SNF complex; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Viral infections; Xenograft Model Antitumor Assays; United Kingdom
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0541-5

Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis -regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients. ARID1A and other SWI/SNF components are critical for response to estrogen-receptor antagonists in breast cancer. SWI/SNF-specific gene knockouts lead to drug resistance and ARID1A mutations are more frequent in resistant tumors from patients.