BAF155 Methylation Drives Metastasis By Hijacking Super-enhancers and Subverting Anti-tumor Immunity

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-enhanceraddicted oncogenes by recruiting BRD4, and repression of interferon / 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 strongl...染色质重塑复合物SWI/SNF的亚基是癌症中最常发生功能失调的基因。然而，目前尚不清楚SWI/SNF亚基的翻译后修饰（post-translational modifications, PTM）如何引发表观遗传功能异常。辅激活因子相关精氨酸甲基转移酶1（coactivator-associated arginine methyltransferase 1, CARM1）对BAF155的精氨酸甲基化可促进三阴性乳腺癌（triple negative breast cancer, TNBC）转移。本研究发现了甲基化BAF155（me-BAF155）在促进肿瘤转移中的双重作用：一是通过招募BRD4激活依赖超级增强子的癌基因，二是抑制干扰素通路基因以削弱宿主免疫应答。对CARM1及BAF155甲基化的药理学抑制，不仅能够抑制一系列癌基因的表达，还可通过增强细胞毒性T细胞的活性与肿瘤浸润性来强化宿主免疫应答。此外，在转移性癌症患者的循环肿瘤细胞中检测到了强阳性的me-BAF155染色信号。尽管CARM1抑制剂的细胞毒性较低，但CARM1抑制剂仍具有强...