Li Xin, Yang Jian, Chen Xia, Cao Dandan, Xu Eugene Yujun
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, China.
J Biomed Res. 2021 Jul 16;35(5):371-382. doi: 10.7555/JBR.35.20210067.
Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis; identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics. Highly conserved RNA-binding protein Pumilio-1 (PUM1) regulates mouse growth and cell proliferation, propelling us to examine its role in cancer. We found human is highly expressed in a diverse group of cancer, including prostate cancer; enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients. Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of at mRNA and protein levels. Knockdown of reduced prostate cancer cell proliferation and colony formation, and subcutaneous injection of knockdown cells led to reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B (CDKN1B) protein expression through increased translation but did not impact its mRNA level, while overexpression of PUM1 reduced CDKN1B protein level. Our finding established a critical role of PUM1 mediated translational control, particularly the PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.
癌症基因表达程序的转录后调控在致癌过程中起着至关重要的作用；确定肿瘤发生的关键调节因子及其分子靶点可能为癌症诊断和治疗提供新策略。高度保守的RNA结合蛋白Pumilio-1（PUM1）调节小鼠生长和细胞增殖，促使我们研究其在癌症中的作用。我们发现人类PUM1在包括前列腺癌在内的多种癌症中高度表达；PUM1表达增强也与前列腺癌患者生存率降低相关。对20个前列腺癌组织进行的详细表达分析显示，PUM1在mRNA和蛋白质水平上表达增强。敲低PUM1可降低前列腺癌细胞增殖和集落形成，皮下注射PUM1敲低细胞可导致肿瘤大小减小。前列腺癌细胞中PUM1的下调通过增加翻译持续提高细胞周期蛋白依赖性激酶抑制剂1B（CDKN1B）蛋白表达，但不影响其mRNA水平，而PUM1的过表达则降低CDKN1B蛋白水平。我们的发现确立了PUM1介导的翻译控制，特别是PUM1-CDKN1B轴，在前列腺癌细胞生长和肿瘤发生中的关键作用。我们提出，PUM1-CDKN1B调控轴可能代表了多种癌症中CDKN1B蛋白表达缺失的一种新机制，以及治疗开发的潜在靶点。
