HMGCS2 enhances invasion and metastasis via direct interaction with PPARα to activate Src signaling in colorectal cancer and oral cancer.

// Shih-Wen Chen 1, * , Chiang-Ting Chou 2, 3, * , Cheng-Chi Chang 1, 4, 5, 6, 7, 8 , Yue-Ju Li 4 , Szu-Ta Chen 9, 10 , I-Ching Lin 11, 12, 13 , Sang-Heng Kok 14, 15 , Shih-Jung Cheng 1, 4, 15 , Jang-Jaer Lee 7 , Tai-Sheng Wu 4 , Min-Liang Kuo 17 , Been-Ren Lin 16 1 Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan 2 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan 3 Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan 4 Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan 5 Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan 6 Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan 7 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 8 Department of Biotechnology, Asia University, Taichung, Taiwan 9 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan 10 Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 11 School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 12 Department of Family Medicine, Changhua Christian Hospital, Changhua, Taiwan 13 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 14 Division of Oral and Maxillofacial Surgery, Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan 15 Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan 16 Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan 17 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan * These authors contributed equally to this work Correspondence to: Been-Ren Lin, email: beenrenlin@ntu.edu.tw Keywords: HMGCS2, PPARα, metastasis, CRC, OSCC Received: May 31, 2016      Accepted: October 21, 2016      Published: November 01, 2016 ABSTRACT Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) is the rate-limiting enzyme of ketogenesis. Growing evidence indicates that HMGCS2 may be involved in cancer progression, but its exact role is largely unknown. In this study, we demonstrate that HMGCS2 mRNA expression is associated with poor clinical prognosis and outcomes in patients with colorectal cancer (CRC) and oral squamous cell carcinoma (OSCC). In vitro , ectopic expression of HMGCS2 enhanced cancer cell motility in a ketogenesis-independent manner. Moreover, HMGCS2 promoted Src activity by directly binding to peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional activator of Src. Taken together, these results suggest that HMGCS2 may serve as a useful prognostic marker and vital target for future therapeutic strategies against advanced cancer.