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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Rao, Shalini V 
Cheeseman, Danya 
Dunn, Shanade 

Abstract

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.

Description

Keywords

Acetylation, Animals, Breast Neoplasms, Cell Cycle Proteins, Cell Proliferation, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Binding Proteins, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Histone Deacetylase 1, Humans, MCF-7 Cells, Mice, Inbred NOD, Transcription Factors, Xenograft Model Antitumor Assays

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

52

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
European Research Council (646876)
ERC Consolidator award (646876), Susan G Komen leadership grant and CRUK Core Funding