BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
02 12 2021
02 12 2021
Historique:
accepted:
26
10
2021
revised:
06
10
2021
received:
16
08
2021
entrez:
5
12
2021
pubmed:
6
12
2021
medline:
11
1
2022
Statut:
ppublish
Résumé
Subunits of the chromatin remodeler SWI/SNF are the most frequently disrupted genes in cancer. However, how post-translational modifications (PTM) of SWI/SNF subunits elicit epigenetic dysfunction remains unknown. Arginine-methylation of BAF155 by coactivator-associated arginine methyltransferase 1 (CARM1) promotes triple-negative breast cancer (TNBC) metastasis. Herein, we discovered the dual roles of methylated-BAF155 (me-BAF155) in promoting tumor metastasis: activation of super-enhancer-addicted oncogenes by recruiting BRD4, and repression of interferon α/γ pathway genes to suppress host immune response. Pharmacological inhibition of CARM1 and BAF155 methylation not only abrogated the expression of an array of oncogenes, but also boosted host immune responses by enhancing the activity and tumor infiltration of cytotoxic T cells. Moreover, strong me-BAF155 staining was detected in circulating tumor cells from metastatic cancer patients. Despite low cytotoxicity, CARM1 inhibitors strongly inhibited TNBC cell migration in vitro, and growth and metastasis in vivo. These findings illustrate a unique mechanism of arginine methylation of a SWI/SNF subunit that drives epigenetic dysregulation, and establishes me-BAF155 as a therapeutic target to enhance immunotherapy efficacy.
Identifiants
pubmed: 34865122
pii: 6431811
doi: 10.1093/nar/gkab1122
pmc: PMC8643633
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
SMARCC1 protein, human
0
Transcription Factors
0
Banques de données
Dryad
['10.5061/dryad.xksn02vgq']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12211-12233Subventions
Organisme : NCI NIH HHS
ID : R01 CA236356
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213293
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NIH HHS
ID : R01 CA213293
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124806
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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