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

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

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
02 2020
Historique:
received: 01 02 2019
accepted: 01 11 2019
pubmed: 9 1 2020
medline: 14 4 2020
entrez: 9 1 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-019-0541-5 PMID: 31913353 PMC: PMC7116647
pubmed: 31913353
doi: 10.1038/s41588-019-0541-5
pii: 10.1038/s41588-019-0541-5
pmc: PMC7116647
mid: EMS84795
doi:

Substances chimiques

ARID1A protein, human 0
BRD4 protein, human 0
Cell Cycle Proteins 0
DNA-Binding Proteins 0
ESR1 protein, human 0
Estrogen Receptor alpha 0
FOXA1 protein, human 0
Hepatocyte Nuclear Factor 3-alpha 0
Transcription Factors 0
HDAC1 protein, human EC 3.5.1.98
Histone Deacetylase 1 EC 3.5.1.98

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

187-197

Subventions

Organisme : Cancer Research UK
ID : A20411
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn
Type : ErratumIn

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Auteurs

Sankari Nagarajan (S)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0001-8748-6223

Shalini V Rao (SV)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.

Joseph Sutton (J)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-8868-2370

Danya Cheeseman (D)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Shanade Dunn (S)

Wellcome Trust Sanger Institute, Hinxton, UK.

Evangelia K Papachristou (EK)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-5835-2055

Jose-Enrique Gonzalez Prada (JG)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Dominique-Laurent Couturier (DL)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Sanjeev Kumar (S)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Kamal Kishore (K)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Chandra Sekhar Reddy Chilamakuri (CSR)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Silvia-Elena Glont (SE)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Emily Archer Goode (E)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Cara Brodie (C)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Naomi Guppy (N)

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Rachael Natrajan (R)

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Alejandra Bruna (A)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Carlos Caldas (C)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0003-3547-1489

Alasdair Russell (A)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Rasmus Siersbæk (R)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Kosuke Yusa (K)

Wellcome Trust Sanger Institute, Hinxton, UK.
Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Igor Chernukhin (I)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.

Jason S Carroll (JS)

CRUK Cambridge Institute, University of Cambridge, Cambridge, UK. Jason.carroll@cruk.cam.ac.uk.
ORCID: 0000-0003-3643-0080

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Classifications MeSH

questionsmedicales.fr › Métabolisme › Acylation › Acétylation › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Eucaryotes › Animaux › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Clustered regularly interspaced short palindromic repeats › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteur alpha des oestrogènes › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Facteur nucléaire hépatocytaire HNF-3 alpha › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Histone Deacetylase 1 › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules MCF-7 › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › ARID1A influences HDAC1/BRD4 activity,...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › ARID1A influences HDAC1/BRD4 activity,...