NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A.
Emerging evidences show that disruption of the circadian rhythm is associated with tumor initiation and progression. Neuronal PAS domain protein 2 (NPAS2), one of the core circadian molecules, has been proved to be a potential prognostic biomarker in colorectal and breast cancers. However, to date, the potential functional roles and molecular mechanisms by which NPAS2 affects cancer cell survival are greatly unclear, especially in hepatocellular carcinoma (HCC). We first investigated the expression of NPAS2 and its clinical significance in HCC. We then systematically explored the role of NPAS2 in HCC cell survival both in vitro and in vivo and the underlying mechanism. NPAS2 was frequently upregulated in HCC, which significantly facilitated cell survival both in vitro and in vivo mainly by promoting cell proliferation and inhibiting mitochondria-dependent intrinsic apoptosis, and thus contributed to poor prognosis of HCC patients. Mechanistically, the survival-promoting role of NPAS2 was mediated by transcriptional upregulation of the CDC25A phosphatase and subsequent dephosphorylation of CDK2/4/6 and Bcl-2, which induced cell proliferation and inhibited cell apoptosis in HCC, respectively. Moreover, BMAL1, another core clock transcription factor, was identified to heterodimerize with NPAS2 to bind to the E-box element in the promoter of CDC25A and be associated with the NPAS2-mediated tumor cell survival in HCC. Our findings demonstrate that NPAS2 has a critical role in HCC cell survival and tumor growth, which is mainly mediated by transcriptional upregulation of CDC25A. Thereby, NPAS2 may serve as a potential therapeutic target in HCC patients.
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Peng
P
Yuan
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Jibin
J
Li
Department of General Surgery, Affiliated Huaihai Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
Feng
F
Zhou
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Qichao
Q
Huang
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Jiansheng
J
Zhang
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Xu
X
Guo
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Zhuomin
Z
Lyu
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Hongxin
H
Zhang
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Jinliang
J
Xing
D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D020687:cdc25 Phosphatases / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D020687:cdc25 Phosphatases; C104264:NPAS2 protein, human; C517004:CDC25A protein, human