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 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. Methods Cell cycle arrest : control, JQ1, TP-064, and JQ1+TP-064 in MDA-MB-468 cells. Annexin V staining for measurement of apoptosis : control, JQ1, and TP-064 in MDA-MB-468 cells. Immune cells infiltration in lung tissue : control, JQ1, EZM2302, and JQ1+EZM2302 treatment in 4T1.2 injection model (Balb/c mice). Immune cells population in blood : control, anti-CD8, EZM2302 and anti-CD8+EZM2302 treatment in 4T1.2 injection model (Balb/c mice, 10, 20, 30 days).染色质重塑复合物SWI/SNF（chromatin remodeler SWI/SNF）的亚基是癌症中最常发生功能失调的基因。然而，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，目前仍不明确。辅因子相关精氨酸甲基转移酶1（coactivator-associated arginine methyltransferase 1, CARM1）介导的BAF155精氨酸甲基化可促进三阴性乳腺癌（triple negative breast cancer, TNBC）转移。本研究揭示了甲基化BAF155（me-BAF155）在促进肿瘤转移中的双重作用：通过招募BRD4激活依赖超级增强子的致癌基因，同时通过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，不仅可阻断一系列致癌基因的表达，还可通过增强细胞毒性T细胞的活性与肿瘤浸润能力，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可检测到强阳性的me-BAF155染色信号。尽管CARM1抑制剂的细胞毒性较低，但其可在体外显著抑制三阴性乳腺癌细胞的迁移，并在体内抑制肿瘤生长与转移。本研究阐明了SWI/SNF亚基的精氨酸甲基化驱动表观遗传紊乱的独特机制，并确立了me-BAF155作为增强免疫治疗疗效的治疗靶点。 实验方法 细胞周期阻滞实验：在MDA-MB-468细胞中设置对照组、JQ1处理组、TP-064处理组及JQ1+TP-064联合处理组。 Annexin V染色检测细胞凋亡：在MDA-MB-468细胞中设置对照组、JQ1处理组及TP-064处理组。 肺组织免疫细胞浸润检测：在4T1.2细胞接种的BALB/c小鼠模型中，设置对照组、JQ1处理组、EZM2302处理组及JQ1+EZM2302联合处理组。 血液免疫细胞群体分析：在4T1.2细胞接种的BALB/c小鼠模型中，设置对照组、抗CD8抗体处理组、EZM2302处理组及抗CD8抗体+EZM2302联合处理组，分别于接种后10、20、30天采集样本进行检测。