ΔNp63α 通过抑制 TGFB2 表达和 RHOA 活性来驱动鳞状细胞癌中的细胞增殖。
ΔNp63α Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell Carcinomas.
机构信息
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Functional Genomics Facility, University of Colorado School of Medicine, Aurora, CO 80045, USA.
出版信息
Cell Rep. 2018 Sep 18;24(12):3224-3236. doi: 10.1016/j.celrep.2018.08.058.
The transcriptional repressor ΔNp63α is a potent oncogene widely overexpressed in squamous cell carcinomas (SCCs) of diverse tissue origins, where it promotes malignant cell proliferation and survival. We report here the results of a genome-wide CRISPR screen to identify pathways controlling ΔNp63α-dependent cell proliferation, which revealed that the small GTPase RHOA blocks cell division upon ΔNp63α knockdown. After ΔNp63α depletion, RHOA activity is increased, and cells undergo RHOA-dependent proliferation arrest along with transcriptome changes indicative of increased TGF-β signaling. Mechanistically, ΔNp63α represses transcription of TGFB2, which induces a cell cycle arrest that is partially dependent on RHOA. Ectopic TGFB2 activates RHOA and impairs SCC proliferation, and TGFB2 neutralization restores cell proliferation during ΔNp63α depletion. Genomic data from tumors demonstrate inactivation of RHOA and the TGFBR2 receptor and ΔNp63α overexpression in more than 80% of lung SCCs. These results reveal a signaling pathway controlling SCC proliferation that is potentially amenable to pharmacological intervention.
转录抑制因子 ΔNp63α 广泛过表达于多种组织来源的鳞状细胞癌（SCC）中，是一种强有力的致癌基因，可促进恶性细胞增殖和存活。我们在此报告了一项全基因组 CRISPR 筛选结果，以鉴定控制 ΔNp63α 依赖性细胞增殖的途径，该研究发现小 GTPase RHOA 在 ΔNp63α 敲低时阻止细胞分裂。在 ΔNp63α 耗竭后，RHOA 活性增加，细胞发生 RHOA 依赖性增殖停滞，并伴有 TGF-β 信号增强的转录组变化。在机制上，ΔNp63α 抑制 TGFB2 的转录，后者诱导细胞周期停滞，部分依赖于 RHOA。外源性 TGFB2 激活 RHOA 并损害 SCC 增殖，而在 ΔNp63α 耗竭期间中和 TGFB2 可恢复细胞增殖。肿瘤的基因组数据表明，超过 80%的肺 SCC 中 RHOA 和 TGFBR2 受体失活以及 ΔNp63α 过表达。这些结果揭示了一种控制 SCC 增殖的信号通路，可能适合药物干预。
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