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.

泛素-蛋白酶体系统调节许多不同的生物过程。它的失调会导致各种疾病，包括但不限于癌症。在这项研究中，基于对几个结直肠癌 (CRC) 数据集中的基因表达的分析，我们表明 FBXL6 是一种特征较差的 F-box 蛋白，在人类 CRC 中被扩增、过表达并与不良预后高度相关病人。从机制上讲，FBXL6 靶向磷酸化 p53 (S315) 以介导其多聚泛素化和蛋白酶体降解，从而抑制 p53 信号传导。FBXL6 耗竭通过诱导细胞周期停滞和细胞凋亡抑制 p53 野生型 (WT) CRC 细胞的增殖。此外，p53 通过结合其核心启动子区域转录抑制 FBXL6 表达。综合起来，