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

Sankari Nagarajan, Shalini V. Rao, Joseph Sutton, Danya Cheeseman, Shanade Dunn, Evangelia K. Papachristou, Jose-enrique Gonzalez Prada, Dominique-laurent Couturier, Sanjeev Kumar, Kamal Kishore, Chandra Sekhar Reddy Chilamakuri, Silvia-elena Glont, Emily Archer Goode, Cara Brodie, Naomi Guppy, Rachael Natrajan, Alejandra Bruna, Carlos Caldas, Alasdair Russell, Rasmus SiersbækKosuke Yusa, Igor Chernukhin, Jason S. Carroll

Research output: Contribution to journalArticlepeer-review

95 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)187-197
JournalNature Genetics
Volume52
Issue number2
Early online date6 Jan 2020
DOIs
Publication statusPublished - 1 Feb 2020

Fingerprint

Dive into the research topics of 'ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response'. Together they form a unique fingerprint.

Cite this