Yu Pan, Shen Xi, Yang Wen, Zhang Yunke, Liu Chunping, Huang Tao
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochem Biophys Res Commun. 2018 Jan 22;495(4):2505-2511. doi: 10.1016/j.bbrc.2017.12.139. Epub 2017 Dec 28.
Dysfunctional cell proliferation and death are the foundation of the malignant biological characteristics of cancers. In this study, we discovered that ZEB1 was positively correlated with hTERT in breast invasive ductal carcinoma samples at both the mRNA and protein levels. Further, our in vitro study in breast cancer cell lines confirmed that ZEB1 regulates hTERT expression at the mRNA and protein levels; thus, hTERT promotes or inhibits telomerase activity, and telomere length is either protected or reduced. Finally, we verified that ZEB1, which mostly functions as a transcriptional repressor, can recruit the co-activator YAP to enhance the transcriptional activation of hTERT. Fascinatingly, instead of acting on E-boxes, the ZEB1/YAP complex tends to function as a transcriptional activator by binding with sequences potentially located in the hTERT promoter. Consequently, our research revealed a new ZEB1-hTERT signaling pathway involved in cell proliferation regulation that has never before been illuminated in breast cancer.
功能失调的细胞增殖和死亡是癌症恶性生物学特征的基础。在本研究中，我们发现，在乳腺浸润性导管癌样本中，ZEB1在mRNA和蛋白质水平上均与hTERT呈正相关。此外，我们在乳腺癌细胞系中的体外研究证实，ZEB1在mRNA和蛋白质水平上调节hTERT表达；因此，hTERT促进或抑制端粒酶活性，端粒长度要么得到保护，要么缩短。最后，我们证实，主要作为转录抑制因子发挥作用的ZEB1可以招募共激活因子YAP，以增强hTERT的转录激活。有趣的是，ZEB1/YAP复合物并非作用于E盒，而是倾向于通过与可能位于hTERT启动子中的序列结合，作为转录激活因子发挥作用。因此，我们的研究揭示了一条新的ZEB1-hTERT信号通路，该通路参与细胞增殖调控，此前在乳腺癌中从未被阐明。
