An hTERT/ZEB1 complex directly regulates E-cadherin to promote epithelial-to-mesenchymal transition (EMT) in colorectal cancer

Yong Qin,Rui Xie,Yu-Yun Wu,Xin Yong,Shi-Ming Yang,Hui Dong,Chang-Jiang Hu,Bo Tang,Yu-Feng Xiao

doi:10.18632/oncotarget.5968

Yong Qin, Rui Xie + Show 7 more

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https://doi.org/10.18632/oncotarget.5968

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Journal: Oncotarget	Publication Date: Oct 20, 2015
Citations: 69	License type: cc-by

Affiliation: Army Medical University

Abstract

In human cancer, high telomerase expression is correlated with tumor aggressiveness and metastatic potential. Telomerase activation occurs through telomerase reverse transcriptase (hTERT) induction, which contributes to malignant transformation by stabilizing telomeres. Previous studies have shown that hTERT can promote tumor invasion and metastasis of gastric cancer, liver cancer and esophageal cancer. Epithelial-to-mesenchymal transition (EMT), a requirement for tumor invasion and metastasis, plays a key role in cancer progression. Although hTERT promotes EMT through Wnt signaling in several cancers, it is unknown if other signaling pathways are involved. In the present study, we found that hTERT and ZEB1 form a complex, which directly binds to the E-cadherin promoter, and then inhibits E-cadherin expression and promots EMT in colorectal cancer cells. hTERT overexpression in HCT116 and SW480 cells could induce E-cadherin down-regulation. However, E-cadherin expression was recovered when ZEB1 function was impaired even during hTERT overexpression. Taken together, our findings suggest that hTERT can promote cancer metastasis by stimulating EMT through the ZEB1 pathway and therefore inhibiting them may prevent cancer progression.

Highlights

Colorectal cancer (CRC) is a major cause of cancer mortality in Western countries as it has a propensity to metastasize [1]
HTERT has been shown to promote Epithelial-to-mesenchymal transition (EMT) in osteosarcoma, ovarian cancer, and gastric cancer [8, 15, 16], it is not known if it promotes EMT in CRC
To investigate how human telomerase reverse transcriptase (hTERT) suppresses E-cadherin promoter activity, we used co-immunoprecipitation experiments to determine if hTERT interacts with zinc-finger E-box binding homeobox1 (ZEB1), and we found a direct interaction between them (Figure 4A), confocal imaging revealed they were co-localized in HCT116 cells (Figure 4B)

Summary

Introduction

Colorectal cancer (CRC) is a major cause of cancer mortality in Western countries as it has a propensity to metastasize [1]. CRC has a low incidence in China, it is becoming the fastest growing cancer with the development of our society [2]. Telomerase is a reverse transcriptase that carries its own templates, and maintains telomere length by synthesizing telomeric DNA repeats. Telomerase maintains chromosome stability and enhances the ability of cells to promote cell immortality [3, 4]. The human telomerase reverse transcriptase (hTERT) is a reverse transcriptase that synthesizes telomeric DNA to maintain and increase telomere length. HTERT which is expressed only in immortalized cells and most tumor cells plays an important role in tumor occurrence and development [5].

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