Rajabi Fatemeh, Liu-Bordes Win-Yan, Pinskaya Marina, Dominika Foretek, Kratassiouk Gueorgui, Pinna Guillaume, Nanni Simona, Farsetti Antonella, Gespach Christian, Londoño-Vallejo Arturo, Groisman Irina
Telomeres and Cancer Laboratory, CNRS, Sorbonne Université, Université PSL, Institut Curie, Paris, France.
Non-Coding RNA, Epigenetic and Genome Fluidity, Sorbonne Université, Université PSL, Institut Curie, Paris, France.
Oncotarget. 2020 Nov 10;11(45):4155-4168. doi: 10.18632/oncotarget.27806.
TWIST1 is a basic helix-loop-helix transcription factor, and one of the master Epithelial-to-Mesenchymal Transition (EMT) regulators. We show that tumor suppressor miR-145-5p controls TWIST1 expression in an immortalized prostate epithelial cell line and in a tumorigenic prostate cancer-derived cell line. Indeed, shRNA-mediated miR-145-5p silencing enhanced TWIST1 expression and induced EMT-associated malignant properties in these cells. However, we discovered that the translational inhibitory effect of miR-145-5p on TWIST1 is lost in 22Rv1, another prostate cancer cell line that intrinsically expresses high levels of the CPEB1 cytoplasmic polyadenylation element binding protein. This translational regulator typically reduces TWIST1 translation efficiency by shortening the TWIST1 mRNA polyA tail. However, our results indicate that the presence of CPEB1 also interferes with the binding of miR-145-5p to the TWIST1 mRNA 3'UTR. Mechanistically, CPEB1 binding to its first cognate site either directly hampers the access to the miR-145-5p response element or redirects the cleavage/polyadenylation machinery to an intermediate polyadenylation site, resulting in the elimination of the miR-145-5p binding site. Taken together, our data support the notion that the tumor suppressive activity of miR-145-5p on TWIST1 translation, consequently on EMT, self-renewal, and migration, depends on the CPEB1 expression status of the cancer cell. A preliminary prospective study using clinical samples suggests that reconsidering the relative status of miR-145-5p/TWIST1 and CPEB1 in the tumors of prostate cancer patients may bear prognostic value.
TWIST1是一种碱性螺旋-环-螺旋转录因子，也是上皮-间质转化（EMT）的主要调节因子之一。我们发现，肿瘤抑制因子miR-145-5p在永生化前列腺上皮细胞系和致瘤性前列腺癌衍生细胞系中控制TWIST1的表达。事实上，shRNA介导的miR-145-5p沉默增强了这些细胞中TWIST1的表达，并诱导了与EMT相关的恶性特性。然而，我们发现，miR-145-5p对TWIST1的翻译抑制作用在另一种前列腺癌细胞系22Rv1中丧失，该细胞系内在表达高水平的CPEB1细胞质聚腺苷酸化元件结合蛋白。这种翻译调节因子通常通过缩短TWIST1 mRNA的polyA尾巴来降低TWIST1的翻译效率。然而，我们的结果表明，CPEB1的存在也会干扰miR-145-5p与TWIST1 mRNA 3'UTR的结合。从机制上讲，CPEB1与其第一个同源位点的结合要么直接阻碍miR-145-5p反应元件的进入，要么将切割/聚腺苷酸化机制重定向到一个中间聚腺苷酸化位点，从而导致miR-145-5p结合位点的消除。综上所述，我们的数据支持这样一种观点，即miR-145-5p对TWIST1翻译进而对EMT、自我更新和迁移的肿瘤抑制活性取决于癌细胞的CPEB1表达状态。一项使用临床样本的初步前瞻性研究表明，重新考虑前列腺癌患者肿瘤中miR-145-5p/TWIST1和CPEB1的相对状态可能具有预后价值。
