BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity.

Autor:	Kim EJ; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Liu P; Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Zhang S; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Donahue K; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Wang Y; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Schehr JL; Department of Medicine, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Wolfe SK; Department of Medicine, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Dickerson A; Department of Stem Cell Biology and Regenerative Medicine, and USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Lu L; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.; Laboratory of Genetics, University of Wisconsin-Madison, Madison WI, USA., Rui L; Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Zhong X; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.; Laboratory of Genetics, University of Wisconsin-Madison, Madison WI, USA., Wisinski KB; Department of Medicine, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Yu M; Department of Stem Cell Biology and Regenerative Medicine, and USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Suzuki A; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Lang JM; Department of Medicine, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Ong IM; Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.; Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA., Xu W; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2021 Dec 02; Vol. 49 (21), pp. 12211-12233.
DOI:	10.1093/nar/gkab1122
Abstrakt:	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. (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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