Eui-Jun Kim^1,5, Peng Liu^4,5, Shengjie Zhang¹, Kristine Donahue^1,5, Yidan Wang^1,5, Jennifer L. Schehr^3,5, Serena K. Wolfe^3,5, Amber Dickerson⁶, Li Lu^7,8, Lixin Rui^2,5, Xuehua Zhong^7,8, Kari B. Wisinski^3,5, Min Yu⁶, Aussie Suzuki^1,5, Joshua M. Lang^3,5, Irene M. Ong^2,4,5 and Wei Xu^1,5,*

¹McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA, ²Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA, ³Department of Medicine, University of Wisconsin, Madison, WI 53706, USA, ⁴Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA, ⁵Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA, ⁶Department 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, ⁷Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA and ⁸Laboratory of Genetics, University of Wisconsin-Madison, Madison WI, USA

^*To whom correspondence should be addressed.
Present address: Shengjie Zhang, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Zhejiang 310022, China.

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.