生物
癌症研究
转移
甲基化
表观遗传学
DNA甲基化
癌症
免疫系统
癌细胞
免疫学
基因
基因表达
遗传学
作者
Eui‐Jun Kim,Peng Liu,Shengjie Zhang,Kristine Donahue,Yidan Wang,Jennifer L. Schehr,Serena K. Wolfe,Amber Dickerson,Li Lü,Rui Li,Xuehua Zhong,Kari B. Wisinski,Min Yu,Aussie Suzuki,Joshua M. Lang,Irene M. Ong,Wei Xu
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI