Circadian Clock Gene NPAS2 promotes reprogramming of glucose metabolism in Hepatocellular Carcinoma cells
作者单位：State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicinethe Fourth Military Medical University Department of Pain TreatmentTangdu Hospitalthe Fourth Military Medical University
会议名称：《2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青年科学家论坛》
会议日期：2017年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：neuronal PAS domain protein 2 circadian rhythm Glycolysis Mitochondrial respiration Hepatocellular carcinoma Tumor growth and metastasis
摘 要：Aims: Emerging evidences show that dysregulation of circadian genes is closely associated with tumor development by participating in the cancer hallmarks of proliferative signaling maintenance, cell death resistance, replicative immortality and metastasis activation. However, whether circadian genes regulates the metabolism reprogramming required for tumor cell proliferation and invasion is unknown. Methods: In the present study, we systematically investigated the role of NPAS2 in the reprogramming of glucose metabolism, as well as its role in the growth and metastasis of HCC cells both in vitro and in vivo. Moreover, the molecular meachnisms governing NPAS2-mediated glucose metabolismreprogramming were further explored. Results: Our results showed that NPAS2, one of the core circadian molecules, significantly contributed to the reprogramming of glucose metabolism through a Hif-1 a-dependent way in HCC cells mainly by two mechanisms. On one hand, NPAS2 upregulated the expression of glycolytic genes HK2, PKM2 and Glut1 by activating transcription of Hif-1 a, which in turn directly activated the aerobic glycolysis. On the other hand, NPAS2 downregulated Peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC-1α) by activating transcription of Hif-1 a, which in turn directly repressed mitochondrial biogenesis and respiration. Moreover, in vitro and in vivo assays indicated that the NPAS2-mediated reprogramming of glucose metabolism reprogramming played a critical role in tumor growth and metastasis of HCC. Conclusion: Our findings demonstrate that NPAS2 plays a critical role in tumor cell metabolism reprogramming regulation, which indicates that NPAS2 may serve as an important therapeutic target to normalize metabolic aberrations responsible for HCC progression.