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

Bo Yu1,2, Jun Su3, Qiqi Shi4

  • 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.

Nature Communications
|April 22, 2022
PubMed

Insights

Smad nuclear-interacting protein 1 (SNIP1) methylation by KMT5A promotes breast cancer growth and metastasis. This KMT5A-mediated methylation activates MARK4, enhancing triple-negative breast cancer (TNBC) progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor linked to TGF-β signaling and c-MYC.
  • The precise role of SNIP1 in tumorigenesis and metastasis remains unclear.
  • Understanding SNIP1 regulation is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which SNIP1 regulates breast cancer progression.
  • To identify post-translational modifications of SNIP1 and their functional consequences.
  • To explore therapeutic strategies targeting SNIP1 in triple-negative breast cancer (TNBC).

Main Methods:

  • Identified SNIP1 as a substrate of lysine methyltransferase KMT5A.
  • Investigated KMT5A-mediated mono-methylation of SNIP1 at K301.
  • Analyzed the interaction between SNIP1, KMT5A, KAT2A, and c-MYC.
  • Assessed the impact on the Hippo kinase cascade and MARK4 transcription.
  • Evaluated therapeutic interventions in TNBC xenograft models.

Main Results:

  • SNIP1 is mono-methylated by KMT5A at K301, promoting breast cancer cell growth, invasion, and lung metastasis.
  • KMT5A-mediated methylation of SNIP1 releases KAT2A, facilitating c-MYC/KAT2A complex formation and recruitment to c-MYC target promoters.
  • This mechanism inhibits the Hippo kinase cascade, upregulating MARK4 and enhancing TNBC metastasis.
  • Co-inhibition of KMT5A and YAP attenuated metastasis and improved survival in preclinical models.

Conclusions:

  • KMT5A-mediated methylation of SNIP1 is a critical regulator of breast cancer progression and metastasis.
  • This epigenetic modification provides a novel therapeutic target for TNBC.
  • Targeting KMT5A catalytic activity and YAP shows promise in combating TNBC metastasis.

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