Circadian clock gene NPAS2 promotes reprogramming of glucose metabolism in hepatocellular carcinoma cells
Authors: Jibin Li
Cheng Chen
Hongxin Zhang
Yiran Hou
Zhaoyong Yan
Tao Yang
Peng Yuan
Jinliang Xing
Jing Zhao
Jiao Mu
Yi Yang
Journal: Cancer Letters (2020)
Discipline: CLINICAL MEDICINE
Keywords: Circadian rhythm; Glycolysis; HCC; Mitochondrial; Neuronal PAS domain protein 2 (NPAS2).
Affiliations: State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China., Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China., Department of Hematology, Xi'an Central Hospital, Xi'an, Shaanxi, 710003, China; Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China., State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China., School of Medicine, Yan'an University, Yan'an, Shaanxi, 716000, China., Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China. Electronic address: ., State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: .

Abstract:  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-1α). Mechanistically, HIF-1α 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-1α-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. 

Retracted: No

PubPeer comments:
 Figure 3D. Much more similar than expected. ![file] , 
 Figure 7B. Image reuse. ![file] , 
 #1 Dear LecithoceraEumenopis, Thank you for your concern. When we saw the question you pointed out in the web, we really shocked. We reviewed the original data and found that the blots in figure 3D just similar but not the same. The original blot is shown in below. ![file] Many thanks for your kind reminding. Sincerely, Jibin Li , 
 #2 Dear LecithoceraEumenopis, Thank you for your concern. When we saw the question you pointed out in the web, we really shocked. We reviewed the original data and found that we accidentally duplicated the image belonging to shNPAS2+HIF1a group to NPAS2+siHIF1a group in Figure 7B. We apologize for the unintentional mistake. And we will remember this lesson in our future work. A corrected version of Figure 7B is shown below. This change does not affect the conclusions of the paper. Corrected Figure 7B. ![file] Many thanks for your kind reminding, we are very sorry for the error of the Figure 7B. We will send a correction of Figure 7B to the editor of the journal and expect to publish Erratum soon. We will be more rigorous in the future scientific research work. Thank you for your interest in our work! Sincerely, Jibin Li ,