A new mechanism of FBXW7 in regulating cancer cell survival discovered

Tumor suppressor p53 acts as a “guardian of the genome” to induce cell growth arrest, apoptosis, and senescence that suppresses tumorigenesis by preventing the growth and division of damaged and potentially precancerous cells. It has been well established that MDM2 (mouse double minute 2 homolog), an E3 ubiquitin ligase, is the critical negative regulator of p53, especially during embryogenesis. In response to DNA damage and other cellular stresses, such as hypoxia or oncogene activation, p53 is induced via stabilization to transcriptionally activate or repress the expression of downstream target genes. Upon the repair of damaged DNA, p53 needs to return to the basal level so that the cell growth arrest can be eliminated and cell-cycle progression will be restored. How p53 is ubiquitinated and degraded remains in the main elusive.

The research team led by ZHAO Yongchao from the First Affiliated Hospital and the Institute of Translational Medicine of Zhejiang University did research into the role of FBXW7 in degrading p53. Their research findings were published in a research article entitled “FBXW7 Confers Radiation Survival by Targeting p53 for Degradation” in the January 14 issue of the journal of Cell Reports.

This study suggests that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 ligase, can interact with and target p53 for polyubiquitination and proteasomal degradation after exposure to ionizing radiation or etoposide. At the mechanistic level, DNA damage activates ATM to phosphorylate p53 on Ser33 and Ser37, which facilitates the FBXW7 binding and the subsequent p53 degradation by SCF^FBXW7. Inactivation of ATM or SCF^FBXW7 by small molecular inhibitors or genetic knockdown/knockout approaches extends the p53 protein half-life upon DNA damage in an MDM2-independent manner. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis.

This study opens up a novel mechanism by which FBXW7 regulates cancer cell survival during radiotherapy or chemotherapy via p53 targeting, thus providing a promising therapy for cancers.