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

Eui Jun Kim, Peng Liu, Shengjie Zhang, Kristine Donahue, Yidan Wang, Jennifer L. Schehr, Serena K. Wolfe, Amber Dickerson, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Min Yu, Aussie Suzuki, Joshua M. Lang, Irene M. Ong, Wei Xu

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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/γpathway 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.

Original languageEnglish
Pages (from-to)12211-12233
Number of pages23
JournalNucleic acids research
Volume49
Issue number21
DOIs
StatePublished - Dec 2 2021

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