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

  • Nat Commun. 2022 Apr 21;13(1):2192. doi: 10.1038/s41467-022-29899-w.
Bo Yu  #  1  2 ,  Jun Su  #  3 ,  Qiqi Shi  #  4 ,  Qing Liu  5 ,  Jun Ma  6 ,  Guoqing Ru  7 ,  Lei Zhang  8 ,  Jian Zhang  9  10  11 ,  Xichun Hu  12  13 ,  Jianming Tang  14
Affiliations
  • 1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
  • 3. Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025, P. R. China.
  • 4. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
  • 5. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China.
  • 6. Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
  • 7. Department of Pathology, Zhejiang Provincial People's Hospital, People' s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, P. R. China.
  • 8. Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
  • 9. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China. [email protected].
  • 10. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China. [email protected].
  • 11. Department of Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China. [email protected].
  • 12. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China. [email protected].
  • 13. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China. [email protected].
  • 14. Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, P. R. China. [email protected].
  • # Contributed equally.
PMID: 35449131 DOI: 10.1038/s41467-022-29899-w
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.