Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Oncogene. 2022 Apr;41(16):2357-2371. doi: 10.1038/s41388-022-02260-7. Epub 2022 Mar 7.
Mutant p53 (mtp53) can exert cancer-promoting activities via "gain-of-function", which has become a popular research target. Although lots of researchers focus on the tumor-suppressor role for p53, the regulation of mutant p53 remains unknown. Here, we report a mechanism by which mtp53 regulate the transcription of Rab coupling protein (RCP) to influence lung cancer behavior. First, we show that RCP is specifically expressed at high levels in lung cancer tissues and cells, and RCP knockout suppresses tumor growth and metastasis. Further mass spectrometry and functional analysis identify that Sp1, Sp3 and Stat3 are the transcriptional activators of RCP. Moreover, p53 is involved in modulating RCP expression in an Sp1/3 dependent manner. Mechanistically, in contrast to wild-type p53 suppression of RCP transcription by decreasing Sp1/3 proteins, TP53 mutations have changed on Sp1/3 expression via "loss-of-function". Surprisingly, the DNA contact mutants of p53 further robustly enhance their binding ability with Sp1/3 to drive RCP expression through the "gain-of-function" activity. Collectively, we reveal a mechanism by which p53 regulating the transcription of RCP to influence lung cancer progression, which provides new insights for treating p53 mutant lung cancer.
突变型 p53（mtp53）可通过“获得功能”发挥致癌作用，这已成为一个热门的研究靶点。尽管许多研究人员关注 p53 的肿瘤抑制作用，但突变型 p53 的调节仍不清楚。在这里，我们报告了一种 mtp53 调节 Rab 连接蛋白（RCP）转录的机制，以影响肺癌行为。首先，我们表明 RCP 在肺癌组织和细胞中特异性高水平表达，并且 RCP 敲除抑制肿瘤生长和转移。进一步的质谱分析和功能分析确定 Sp1、Sp3 和 Stat3 是 RCP 的转录激活子。此外，p53 参与调节 RCP 表达，依赖于 Sp1/3。从机制上讲，与野生型 p53 通过降低 Sp1/3 蛋白抑制 RCP 转录相反，TP53 突变通过“功能丧失”改变了 Sp1/3 的表达。令人惊讶的是，p53 的 DNA 接触突变体通过“获得功能”活性进一步增强了与 Sp1/3 的结合能力，从而驱动 RCP 的表达。总之，我们揭示了 p53 调节 RCP 转录以影响肺癌进展的机制，为治疗 p53 突变型肺癌提供了新的见解。
