FBXL6 degrades phosphorylated p53 to promote tumor growth
FBXL6 degrades phosphorylated p53 to promote tumor growth
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FBXL6 降解磷酸化 p53 以促进肿瘤生长。
DOI：
10.1038/s41418-021-00739-6
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发表时间：
2021-02-10
影响因子：
12.4
通讯作者：
Li, Youjun
中科院分区：
文献类型：
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作者：
Li, Yajun;Cui, Kaisa;Li, Youjun
泛素-蛋白酶体系统调节许多不同的生物过程。其失调导致各种疾病，包括但不限于癌症。在这项研究中，基于对几种结直肠癌（CRC）数据集的基因表达分析，我们发现FBXL 6是一种特征不佳的F-box蛋白，在人类CRC患者中扩增，过度表达，并与预后不良高度相关。在机制上，FBXL 6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。FBXL 6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而转录抑制FBXL 6表达。总之，这些结果将FBXL 6-p53的前馈环鉴定为CRC治疗的潜在治疗靶点。
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.