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Phosphorylation of MSX1 controls tumorigenesis and bone development through targeting FBXW7 degradation

Yenan Yang1, Xiang Jia2, Yu Peng2

  • 1State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438, China; School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong, 999077, China.

Cancer Letters
|July 25, 2025
PubMed

Insights

MSX1 degradation of tumor suppressor FBXW7 drives gastric cancer. Inhibiting CDK1 and chemotherapy synergistically reduced tumor growth, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Developmental Biology

Background:

  • MSX1 is a developmental transcription factor re-activated in cancers, but its oncogenic role is unclear.
  • FBXW7 is a tumor suppressor protein targeted by MSX1 in cancer.
  • Understanding the MSX1-FBXW7 interaction is crucial for cancer therapy.

Purpose of the Study:

  • To elucidate the mechanism by which MSX1 promotes cancer.
  • To investigate the role of MSX1 phosphorylation in FBXW7 degradation.
  • To develop a targeted therapeutic strategy for gastric cancer.

Main Methods:

  • Investigated MSX1 phosphorylation at Ser136 by CDK1.
  • Utilized MSX1 phosphorylation mimic (S136D) and non-phosphorylatable (S136A) mutants.
  • Validated the MSX1-FBXW7 axis in clinical gastric cancer samples.
  • Developed and tested a combination therapy of chemotherapy and CDK1 inhibition.
  • Generated and analyzed an S136A knock-in mouse model.

Main Results:

  • MSX1 promotes FBXW7 degradation via CDK1-mediated phosphorylation at Ser136.
  • Phosphorylation of MSX1 leads to FBXW7 degradation, accumulating oncogenic substrates c-MYC and MCL1.
  • This axis drives gastric cancer growth and chemoresistance.
  • Combined chemotherapy and CDK1 inhibition synergistically suppressed gastric cancer.
  • S136A knock-in mice showed protection against gastric tumorigenesis but had developmental defects.

Conclusions:

  • The pMSX1-FBXW7 axis is a key driver of gastric cancer.
  • Targeting this axis offers a promising therapeutic strategy for gastric cancer.
  • MSX1 phosphorylation plays a dual role in both cancer development and mammalian development.
Keywords:
Combinatorial targeted therapyDevelopmental regulationFBXW7 degradationGastric cancerMSX1 phosphorylation

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