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

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ICR Authors

Natrajan, Rachael
 Bruna Cabot, Alejandra

Authors

Nagarajan, S
Rao, SV
Sutton, J
Cheeseman, D
Dunn, S
Papachristou, EK
Prada, J-EG
Couturier, D-L
Kumar, S
Kishore, K
Chilamakuri, CSR
Glont, S-E
Archer Goode, E
Brodie, C
Guppy, N
Natrajan, R
Bruna, A
Caldas, C
Russell, A
Siersbæk, R
Yusa, K
Chernukhin, I
Carroll, JS

Document Type

Journal Article

Date

2020-02-01

Date Accepted

2019-11-01

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.

Citation

Nature genetics, 2020, 52 (2), pp. 187 - 197

DOI

10.1038/s41588-019-0541-5

URI

https://repository.icr.ac.uk/handle/internal/4682

Rights

https://www.rioxx.net/licenses/all-rights-reserved

Source Title

Publisher

NATURE PORTFOLIO

ISSN

1061-4036

eISSN

1546-1718

Collections

Cancer Biology

Research Team

Preclinical Modelling of Paediatric Cancer Evolution
Preclinical Modelling of Paediatric Cancer Evolution

Notes