BMAL1 Knockdown Leans Epithelial-Mesenchymal Balance toward Epithelial Properties and Decreases the Chemoresistance of Colon Carcinoma Cells.

Yuan Zhang,Hervé Acloque,Éva Hadadi,Yao Xiang,Julien Giron-Michel,Annabelle Ballesta,Lucas Eduardo Botelho De Souza,Adlen Foudi,Christophe Desterke,Yunhua Chang,Aurore Devocelle

doi:10.3390/ijms22105247

Abstract

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial–mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial–mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.

Highlights

Colorectal cancer (CRC) is one of the most common cancers and represents the fourth leading cause of cancer death worldwide
Disruption of the circadian clock plays a crucial role in carcinogenesis, in particular in human CRC [11,12,13]
We provided evidence, for the first time, that BMAL1KD promotes mesenchymal-to-epithelial transition (MET)-like changes of colorectal carcinoma cell lines

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancers and represents the fourth leading cause of cancer death worldwide. Metastasis in liver and lung represents one of the main causes of CRC-related mortality [2]. An insight into the molecular events driving metastasis, the enhanced invasiveness and therapeutic resistance, is crucial for developing some novel treatment regimens to combat CRC. One such critical event is the epithelial-to-mesenchymal transition (EMT), an early step of CRC metastasis, by which polarized epithelial cells lose their cell polarity and cell–cell adhesion but gain mesenchymal cell properties with enhanced migratory capacity, invasiveness, metastatic potential, and drug resistance [3].

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Results

Conclusion