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...

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Bibliographic Details
Published in:Oncotarget 2017-04, Vol.8 (14), p.22460-22476
Main Authors: Chen, Shih-Wen, Chou, Chiang-Ting, Chang, Cheng-Chi, Li, Yue-Ju, Chen, Szu-Ta, Lin, I-Ching, Kok, Sang-Heng, Cheng, Shih-Jung, Lee, Jang-Jaer, Wu, Tai-Sheng, Kuo, Min-Liang, Lin, Been-Ren
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Squamous Cell - diagnosis
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - mortality
Cell Movement
Colorectal Neoplasms - diagnosis
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - mortality
Female
Humans
Hydroxymethylglutaryl-CoA Synthase - genetics
Hydroxymethylglutaryl-CoA Synthase - metabolism
Mice
Mice, SCID
Mitochondria - physiology
Mouth Neoplasms - diagnosis
Mouth Neoplasms - metabolism
Mouth Neoplasms - mortality
PPAR alpha - metabolism
Prognosis
Proto-Oncogene Proteins pp60(c-src) - genetics
Proto-Oncogene Proteins pp60(c-src) - metabolism
Research Paper
RNA, Small Interfering - genetics
Survival Analysis
Tumor Cells, Cultured
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.13006