Circadian clock gene NPAS2 promotes reprogramming of glucose metabolism in hepatocellular carcinoma cells

Emerging evidences show that dysregulation of circadian genes is closely associated with tumorigenesis. However, whether circadian genes regulate the reprogramming of metabolism in tumor cells is largely unknown. Here, we showed that NPAS2, one of the core circadian molecules, significantly contributed to the reprogramming of glucose metabolism mainly through two mechanisms. On the one hand, NPAS2 upregulated the expression of glycolytic genes GLUT1, HK2, GPI, ALDOA, ENO2, PKM2 and MCT4. On the other hand, NPAS2 downregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). Mechanistically, HIF-1 alpha was found to be a direct transcriptional target of NPAS2, which mediated both the upregulation of glycolytic genes and downregulation of mitochondrial biogenesis in HCC cells. In addition, we found that upregulation of NPAS2 expression was mainly due to the downregulation of miR-199b-5p. In vitro and in vivo assays further indicated that HIF-1 alpha-mediated reprogramming of glucose metabolism played a critical role in NPAS2-regulated growth and metastasis of HCC cells. Our findings demonstrate that NPAS2 plays a critical role in glucose metabolism reprogramming, suggesting that NPAS2 may serve as a potential therapeutic target in HCC.