Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
Medical Research Institute, Wuhan University, Wuhan, China.
Cell Death Differ. 2021 Jul;28(7):2112-2125. doi: 10.1038/s41418-021-00739-6. Epub 2021 Feb 10.
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-蛋白酶体系统调节着许多不同的生物学过程。其失调会导致多种疾病，包括但不限于癌症。在这项研究中，我们基于对几个结直肠癌（CRC）数据集的基因表达分析，表明 FBXL6 是一种特征尚不明确的 F-box 蛋白，在人类 CRC 患者中存在扩增、过表达，并与不良预后高度相关。在机制上，FBXL6 将磷酸化的 p53（S315）作为靶标，介导其多泛素化和蛋白酶体降解，从而抑制 p53 信号通路。FBXL6 的缺失通过诱导细胞周期停滞和细胞凋亡来抑制 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 的表达。综上所述，这些结果确定了 FBXL6-p53 的正反馈环作为 CRC 治疗的潜在治疗靶点。
