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

Author

Listed:
  • Bo Yu

    (Fudan University Shanghai Cancer Center
    Fudan University)

  • 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
    Fudan University
    Fudan University Shanghai Cancer Center)

  • Xichun Hu

    (Fudan University Shanghai Cancer Center
    Fudan University)

  • Jianming Tang

    (The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University)

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.

Suggested Citation

  • Bo Yu & Jun Su & Qiqi Shi & Qing Liu & Jun Ma & Guoqing Ru & Lei Zhang & Jian Zhang & Xichun Hu & Jianming Tang, 2022. "KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29899-w
    DOI: 10.1038/s41467-022-29899-w
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    References listed on IDEAS

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    1. Youzhou Sang & Yanxin Li & Yingwen Zhang & Angel A. Alvarez & Bo Yu & Weiwei Zhang & Bo Hu & Shi-Yuan Cheng & Haizhong Feng, 2019. "CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Qi Fei & Ke Shang & Jianhua Zhang & Shannon Chuai & Desheng Kong & Tianlun Zhou & Shijun Fu & Ying Liang & Chong Li & Zhi Chen & Yuan Zhao & Zhengtian Yu & Zheng Huang & Min Hu & Haiyan Ying & Zhui Ch, 2015. "Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    3. Yugang Wang & Yusong R. Guo & Ke Liu & Zheng Yin & Rui Liu & Yan Xia & Lin Tan & Peiying Yang & Jong-Ho Lee & Xin-jian Li & David Hawke & Yanhua Zheng & Xu Qian & Jianxin Lyu & Jie He & Dongming Xing , 2017. "KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase," Nature, Nature, vol. 552(7684), pages 273-277, December.
    4. Pawel K. Mazur & Nicolas Reynoird & Purvesh Khatri & Pascal W. T. C. Jansen & Alex W. Wilkinson & Shichong Liu & Olena Barbash & Glenn S. Van Aller & Michael Huddleston & Dashyant Dhanak & Peter J. Tu, 2014. "SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer," Nature, Nature, vol. 510(7504), pages 283-287, June.
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    Cited by:

    1. Sara Weirich & Albert Jeltsch, 2023. "Limited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    2. Yurika Matsui & Mohamed Nadhir Djekidel & Katherine Lindsay & Parimal Samir & Nina Connolly & Gang Wu & Xiaoyang Yang & Yiping Fan & Beisi Xu & Jamy C. Peng, 2023. "SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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