FBXL6 degrades phosphorylated p53 to promote tumor growth.

The ubiquitin-proteasome system regulates many distinct biological processes. Its dysregulation causes various diseases, including but not limited to cancer. In this study, based on the analysis of gene expression in several colorectal cancer (CRC) datasets, we show that FBXL6, a poorly-characterized F-box protein, is amplified, over-expressed, and highly correlated with poor prognosis in human CRC patients. Mechanistically, FBXL6 targets phospho-p53 (S315) to mediate its polyubiquitination and proteasomal degradation, thereby inhibiting p53 signaling. FBXL6 depletion inhibits proliferation of p53 wild-type (WT) CRC cells by inducing cell cycle arrest and apoptosis. Furthermore, p53 transcriptionally suppresses FBXL6 expression by binding its core promoter region. Taken together, these results identify the feed-forward loop of FBXL6-p53 as a potential therapeutic target for CRC treatments.