HMGCS2 enhances invasion and metastasis via direct interaction with PPARα to activate Src signaling in colorectal cancer and oral cancer.
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.
Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
Shih-Wen
SW
Chen
Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi Campus, Taiwan.|Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi Campus, Taiwan.
Chiang-Ting
CT
Chou
Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.|Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan.|Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
Cheng-Chi
CC
Chang
Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
Yue-Ju
YJ
Li
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Szu-Ta
ST
Chen
School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Family Medicine, Changhua Christian Hospital, Changhua, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
I-Ching
IC
Lin
Division of Oral and Maxillofacial Surgery, Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.|Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Sang-Heng
SH
Kok
Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.|Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Shih-Jung
SJ
Cheng
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Jang-Jaer
JJ
Lee
Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
Tai-Sheng
TS
Wu
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Min-Liang
ML
Kuo
Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Been-Ren
BR
Lin
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000502:physiology*; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D047493:PPAR alpha / Q000378:metabolism; D011379:Prognosis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
C000599408:HMGCS2 protein, human; D047493:PPAR alpha; D034741:RNA, Small Interfering; D006904:Hydroxymethylglutaryl-CoA Synthase; D016392:Proto-Oncogene Proteins pp60(c-src)
CRC; HMGCS2; OSCC; PPARα; metastasis