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).