Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth

• Published in: Cell reports (Cambridge) 2014-09, Vol.8 (5), p.1461-1474
• Main Authors: Wang, Lei, Xiong, Hua, Wu, Fengxia, Zhang, Yingjie, Wang, Ji, Zhao, Liyan, Guo, Xiaolan, Chang, Li-Ju, Zhang, Yong, You, M. James, Koochekpour, Shahriar, Saleem, Mohammad, Huang, Haojie, Lu, Junxuan, Deng, Yibin
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - metabolism; Cell Line, Tumor; Fibroblasts - metabolism; Gene Deletion; Glycolysis; Hexokinase - genetics; Hexokinase - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes - metabolism; Phosphoproteins - metabolism; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Biosynthesis; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.07.053

Accumulating evidence suggests that codeletion of the tumor suppressor genes Pten and p53 plays a crucial role in the development of castration-resistant prostate cancer in vivo. However, the molecular mechanism underlying Pten-/p53-deficiency-driven prostate tumorigenesis remains incompletely understood. Building upon insights gained from our studies with Pten-/p53-deficient mouse embryonic fibroblasts (MEFs), we report here that hexokinase 2 (HK2) is selectively upregulated by the combined loss of Pten and p53 in prostate cancer cells. Mechanistically, Pten deletion increases HK2 mRNA translation through the activation of the AKT-mTORC1-4EBP1 axis, and p53 loss enhances HK2 mRNA stability through the inhibition of miR143 biogenesis. Genetic studies demonstrate that HK2-mediated aerobic glycolysis, known as the Warburg effect, is required for Pten-/p53-deficiency-driven tumor growth in xenograft mouse models of prostate cancer. Our findings suggest that HK2 might be a therapeutic target for prostate cancer patients carrying Pten and p53 mutations. [Display omitted] •HK2 is upregulated in prostate cancer cells harboring Pten/p53 mutations•Pten deletion increases HK2 mRNA translation by activating the AKT-mTORC1 axis•p53 loss enhances HK2 mRNA by reducing miR143-mediated mRNA degradation•HK2 is required for Pten-/p53-deficiency-driven prostate tumor growth in vivo The molecular mechanism underlying how loss of tumor suppressor genes Pten and p53 drives prostate tumorigenesis is not well understood. Here, Wang et al. find that Pten/p53 deficiency in prostate cancers selectively enhances expression of hexokinase 2 (HK2) through posttranscriptional and translational regulation. Genetic studies demonstrate that the HK2-mediated Warburg effect is required for Pten-/p53-deficiency-driven prostate tumor growth in vivo. Thus, HK2 might be a potential therapeutic target for prostate cancer patients harboring Pten and p53 mutations.