Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation

// Tong-Hong Wang 1, 2, 3 , Chi-Hao Wu 4 , Chau-Ting Yeh 3 , Shih-Chi Su 5 , Shih-Min Hsia 6 , Kung-Hao Liang 3 , Chin-Chuan Chen 1, 7 , Chuen Hsueh 1, 8 and Chi-Yuan Chen 1, 2 1 Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan 2 Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan 3 Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan 4 Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan 5 Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan 6 School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan 7 Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan, Taiwan 8 Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan Correspondence to: Chuen Hsueh, email: ch9211@adm.cgmh.org.tw Chi-Yuan Chen, email: d49417002@gmail.com Keywords: melatonin, hepatocellular carcinoma, epithelial-mesenchymal transition, lncRNA-CPS1-IT1, HIF-1α Received: April 14, 2017      Accepted: June 10, 2017      Published: July 18, 2017 ABSTRACT Melatonin is the primary pineal hormone that relays light/dark cycle information to the circadian system. It was recently reported to exert intrinsic antitumor activity in various cancers. However, the regulatory mechanisms underlying the antitumor activity of melatonin are poorly understood. Moreover, a limited number of studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), a major life-threatening malignancy in both sexes in Taiwan. In this study, we investigated the antitumor effects of melatonin in HCC and explored the regulatory mechanisms underlying these effects. We observed that melatonin significantly inhibited the proliferation, migration, and invasion of HCC cells and significantly induced the expression of the transcription factor FOXA2 in HCC cells. This increase in FOXA2 expression resulted in upregulation of lncRNA-CPS1 intronic transcript 1 (CPS1-IT1), which reduced HIF-1α activity and consequently resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo experiments confirmed that melatonin exerts tumor suppressive effects by reducing tumor growth. In conclusion, our findings suggested that melatonin inhibited HCC progression by reducing lncRNA-CPS1-IT1-mediated EMT suppression and indicated that melatonin could be a promising treatment for HCC.