Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition

Abstract

// Md. Asaduzzaman Khan 1 , Mousumi Tania 1 , Chunli Wei 1 , Zhiqiang Mei 1 , Shelly Fu 1, 2 , Jingliang Cheng 1 , Jianming Xu 1, 3, 4 , Junjiang Fu 1 1 Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Sichuan Medical University, Luzhou, Sichuan, China 2 Michael E. DeBakey High School for Health Professions, Houston, TX, USA 3 College of Basic Medical Sciences and Institute for Cancer Medicine, Sichuan Medical University, Luzhou, Sichuan, China 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA Correspondence to: Junjiang Fu, e-mail: fujunjiang@hotmail.com , e-mail: fujunjiang@lzmc.edu.cn Keywords: thymoquinone, cancer metastasis, TWIST1, epithelial to mesenchymal transition, DNA methylation Received: February 10, 2015      Accepted: May 06, 2015      Published: May 19, 2015 ABSTRACT Proteins that promote epithelial to mesenchymal transition (EMT) are associated with cancer metastasis. Inhibition of EMT regulators may be a promising approach in cancer therapy. In this study, Thymoquinone (TQ) was used to treat cancer cell lines to investigate its effects on EMT-regulatory proteins and cancer metastasis. We show that TQ inhibited cancer cell growth, migration and invasion in a dose-dependent manner. At the molecular level, TQ treatment decreased the transcriptional activity of the TWIST1 promoter and the mRNA expression of TWIST1, an EMT-promoting transcription factor. Accordingly, TQ treatment also decreased the expression of TWIST1-upregulated genes such as N-Cadherin and increased the expression of TWIST1-repressed genes such as E-Cadherin, resulting in a reduction of cell migration and invasion. TQ treatment also inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mice but partially attenuated the migration and invasion in TWIST1-overexpressed cell lines. Furthermore, we found that TQ treatment enhanced the promoter DNA methylation of the TWIST1 gene in BT 549 cells. Together, these results demonstrate that TQ treatment inhibits TWIST1 promoter activity and decreases its expression, leading to the inhibition of cancer cell migration, invasion and metastasis. These findings suggest TQ as a potential small molecular inhibitor of cancer growth and metastasis.