KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling

Bo Yu, Jun Su, Qiqi Shi, Qing Liu, Jun Ma, Guoqing Ru, Lei Zhang, Jian Zhang (), Xichun Hu () and Jianming Tang ()
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Bo Yu: Fudan University Shanghai Cancer Center
Jun Su: Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
Qiqi Shi: Shanghai Jiao Tong University
Qing Liu: Fudan University
Jun Ma: Fudan University
Guoqing Ru: People’ s Hospital of Hangzhou Medical College
Lei Zhang: Shanghai Jiao Tong University
Jian Zhang: Fudan University Shanghai Cancer Center
Xichun Hu: Fudan University Shanghai Cancer Center
Jianming Tang: The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor related to the TGF-β signaling pathway and associates with c-MYC, a key regulator of cell proliferation and tumor development. Currently, the mechanism by which SNIP1 regulates tumorigenesis and cancer metastasis is unknown. Here, we identify that SNIP1 is a non-histone substrate of lysine methyltransferase KMT5A, which undergoes KMT5A-mediated mono-methylation to promote breast cancer cell growth, invasion and lung metastasis. Mechanistically, we show KMT5A-mediated K301 methylation of SNIP1 represents a sensing signal to release histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, and the recruitment of c-MYC/KAT2A complex to promoter of c-MYC targets. This event ultimately inhibits the Hippo kinase cascade to enhance triple-negative breast cancer (TNBC) metastasis by transcriptionally activating MARK4. Co-inhibition of KMT5A catalytic activity and YAP in TNBC xenograft-bearing animals attenuates breast cancer metastasis and increases survival. Collectively, this study presents an KMT5A methylation-dependent regulatory mechanism governing oncogenic function of SNIP1.

Date: 2022
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DOI: 10.1038/s41467-022-29899-w

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