BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity-Reference-Cited by-同舟云学术

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

Published:2021-11-19 Issue:21 Volume:49 Page:12211-12233
ISSN:0305-1048
Container-title:Nucleic Acids Research
language:en
Short-container-title:

Author:

Kim Eui-Jun¹²,Liu Peng³²,Zhang Shengjie¹,Donahue Kristine¹²,Wang Yidan¹²,Schehr Jennifer L⁴²,Wolfe Serena K⁴²,Dickerson Amber⁵,Lu Li⁶⁷,Rui Lixin⁸²,Zhong Xuehua⁶⁷^ORCID,Wisinski Kari B⁴²,Yu Min⁵,Suzuki Aussie¹²,Lang Joshua M⁴²,Ong Irene M⁸³²,Xu Wei¹²^ORCID

Affiliation:

1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA

2. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53706, USA

3. Department of Biostatistics and Medical Informatics. School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA

4. Department of Medicine, University of Wisconsin, Madison, WI 53706, USA

5. 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

6. Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA

7. Laboratory of Genetics, University of Wisconsin-Madison, Madison WI, USA

8. Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA

Abstract

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/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.

Funder

National Institutes of Health

National Cancer Institute

NIH

Susan G. Komen Postdoctoral Fellowship

Publisher

Oxford University Press (OUP)

Subject

Genetics

Link

https://academic.oup.com/nar/article-pdf/49/21/12211/41503692/gkab1122.pdf

Reference56 articles.