Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts

• Published in: Cellular signalling 2014-10, Vol.26 (10), p.2210-2216
• Main Authors: Hu, Jun-wei, Sun, Pan, Zhang, Dao-xiang, Xiong, Wu-jun, Mi, Jun
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Base Sequence; Cancer-associated fibroblast; CDK2; Cells, Cultured; Cyclin-Dependent Kinase 2 - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic - drug effects; HEK293 Cells; Hexokinase - antagonists & inhibitors; Hexokinase - genetics; Hexokinase - metabolism; HK2; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; miR-182; Phosphorylation; RNA Interference; RNA, Small Interfering - metabolism; S Phase Cell Cycle Checkpoints; Sequence Alignment; Signal Transduction; Smad Proteins - antagonists & inhibitors; Smad Proteins - genetics; Smad Proteins - metabolism; Transforming Growth Factor beta1 - pharmacology
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2014.04.015

Hexokinase 2 (HK2), a pivotal glycolytic enzyme, is often overexpressed in tumor cells and contributes to glycolysis. Emerging evidence has suggested that glycolysis is also enhanced in cancer-associated fibroblasts (CAF). However, it is not clear whether HK2 is involved in enhanced glycolysis in CAFs or what role HK2 plays in the CAFs. In this study, both time course experiments and dose response experiments demonstrated that the protein and mRNA levels of HK2 increase in CAF cells, according to western blot and quantitative PCR analyses, respectively. Additionally, miR-182 targets the 3′ UTR of HK2, and its overexpression results in the degradation of HK2 mRNA, which eventually reduces the level of HK2 protein. On the other hand, knockdown of miR-182 increased the expression of HK2. Most importantly, HK2 regulated the protein level and T14 phosphorylation of CDK2, and knockdown of HK2 resulted in a G1 phase cell cycle arrest. These observations suggest that HK2 plays important roles in glycolysis regulation and in cell cycle checkpoint activation. •miR-182 decreases the expression of HK2.•HK2 knockdown caused a G1 phase cell cycle arrest through regulating phosphorylation of CDK2 (Thr14).•HK2 plays important roles in glycolysis and cell cycle progression.