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

Abstract

The transcription factor MSX1, typically expressed in early development but not in most adult tissues, is often re-activated in various cancers, although its underlying oncogenic mechanisms remain elusive. Here, we found that MSX1 promotes the degradation of FBXW7, an E3 ligase and tumor suppressor, through the CDK1-mediated phosphorylation of MSX1 at Ser136. The phosphorylation mimic MSX1 S136D mutant, but not the dephosphorylated S136A mutant, degrades FBXW7 and results in the accumulation of its substrates, including c-MYC and MCL1, ultimately leading to gastric cancer growth and resistance to apoptosis. As the pMSX1–FBXW7 oncogenic axis was validated in clinical gastric cancer samples, we then developed a therapeutic strategy combining chemotherapy with CDK1 inhibition, which synergistically inhibited the gastric cancer growth. Remarkably, the generated S136A knock-in mouse model showed significant protection against carcinogen-induced gastric tumorigenesis, while also exhibited defective limb and skull dysraphism. Collectively, these findings unraveled the importance of pMSX1–FBXW7 axis for both cancer and mammalian development.