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

Eui Jun Kim; Peng Liu; Shengjie Zhang; Kristine Donahue; Yidan Wang; Jennifer L. Schehr; Serena K. Wolfe; Amber Dickerson; Li Lu; Lixin Rui; Xuehua Zhong; Kari B. Wisinski; Min Yu; Aussie Suzuki; Joshua M. Lang; Irene M. Ong; Wei Xu

doi:10.1093/nar/gkab1122

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

Eui Jun Kim, Peng Liu, Shengjie Zhang, Kristine Donahue, Yidan Wang, Jennifer L. Schehr, Serena K. Wolfe, Amber Dickerson, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Min Yu, Aussie Suzuki, Joshua M. Lang, Irene M. Ong, Wei Xu

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32 Scopus citations

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/γpathway 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.

Original language	English
Pages (from-to)	12211-12233
Number of pages	23
Journal	Nucleic acids research
Volume	49
Issue number	21
DOIs	https://doi.org/10.1093/nar/gkab1122
State	Published - Dec 2 2021

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Kim, E. J., Liu, P., Zhang, S., Donahue, K., Wang, Y., Schehr, J. L., Wolfe, S. K., Dickerson, A., Lu, L., Rui, L., Zhong, X., Wisinski, K. B., Yu, M., Suzuki, A., Lang, J. M., Ong, I. M., & Xu, W. (2021). BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity. Nucleic acids research, 49(21), 12211-12233. https://doi.org/10.1093/nar/gkab1122

@article{aec75902b6244140a5872ccf1062f408,

title = "BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity",

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/γpathway 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.",

author = "Kim, {Eui Jun} and Peng Liu and Shengjie Zhang and Kristine Donahue and Yidan Wang and Schehr, {Jennifer L.} and Wolfe, {Serena K.} and Amber Dickerson and Li Lu and Lixin Rui and Xuehua Zhong and Wisinski, {Kari B.} and Min Yu and Aussie Suzuki and Lang, {Joshua M.} and Ong, {Irene M.} and Wei Xu",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",

year = "2021",

month = dec,

day = "2",

doi = "10.1093/nar/gkab1122",

language = "English",

volume = "49",

pages = "12211--12233",

journal = "Nucleic acids research",

issn = "0305-1048",

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Kim, EJ, Liu, P, Zhang, S, Donahue, K, Wang, Y, Schehr, JL, Wolfe, SK, Dickerson, A, Lu, L, Rui, L, Zhong, X, Wisinski, KB, Yu, M, Suzuki, A, Lang, JM, Ong, IM & Xu, W 2021, 'BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity', Nucleic acids research, vol. 49, no. 21, pp. 12211-12233. https://doi.org/10.1093/nar/gkab1122

TY - JOUR

T1 - BAF155 methylation drives metastasis by hijacking super-enhancers and subverting anti-tumor immunity

AU - Kim, Eui Jun

AU - Liu, Peng

AU - Zhang, Shengjie

AU - Donahue, Kristine

AU - Wang, Yidan

AU - Schehr, Jennifer L.

AU - Wolfe, Serena K.

AU - Dickerson, Amber

AU - Lu, Li

AU - Rui, Lixin

AU - Zhong, Xuehua

AU - Wisinski, Kari B.

AU - Yu, Min

AU - Suzuki, Aussie

AU - Lang, Joshua M.

AU - Ong, Irene M.

AU - Xu, Wei

PY - 2021/12/2

Y1 - 2021/12/2

N2 - 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/γpathway 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.

AB - 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/γpathway 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.

UR - http://www.scopus.com/inward/record.url?scp=85122304506&partnerID=8YFLogxK

U2 - 10.1093/nar/gkab1122

DO - 10.1093/nar/gkab1122

M3 - Article

C2 - 34865122

AN - SCOPUS:85122304506

SN - 0305-1048

VL - 49

SP - 12211

EP - 12233

JO - Nucleic acids research

JF - Nucleic acids research

IS - 21

ER -

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

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