Nat Comm_C8orf4 negatively regulates self-renewal of liver cancer stem cell.pdf

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Nat Comm_C8orf4 negatively regulates self-renewal of liver cancer stem cell.pdf

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Nat Comm_C8orf4 negatively regulates self-renewal of liver cancer stem cell

ARTICLE Received 23 Jan 2015 | Accepted 7 Apr 2015 | Published 19 May 2015 C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling Pingping Zhu1,2, Yanying Wang2, Ying Du2, Lei He3, Guanling Huang2,4, Geng Zhang2, Xinlong Yan2 Zusen Fan2,4 Liver cancer stem cells (CSCs) harbour self-renewal and differentiation properties, accounting for chemotherapy resistance and recurrence. However, the molecular mechanisms to sustain liver CSCs remain largely unknown. In this study, based on analysis of several hepatocellular carcinoma (HCC) transcriptome datasets and our experimental data, we find that C8orf4 is weakly expressed in HCC tumours and liver CSCs. C8orf4 attenuates the self-renewal capacity of liver CSCs and tumour propagation. We show that NOTCH2 is activated in liver CSCs. C8orf4 is located in the cytoplasm of HCC tumour cells and associates with the NOTCH2 intracellular domain, which impedes the nuclear translocation of N2ICD. C8orf4 deletion causes the nuclear translocation of N2ICD that triggers the NOTCH2 signalling, which sustains the stemness of liver CSCs. Finally, NOTCH2 activation levels are consistent with clinical severity and prognosis of HCC patients. Altogether, C8orf4 negatively regulates the self-renewal of liver CSCs via suppression of NOTCH2 signalling. DOI: 10.1038/ncomms8122 OPEN 1 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. 2 Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. 3 Department of Hepatobiliary Surgery, PLA General Hospital, Beijing 100853, China. 4 University of Chinese Academy of Sciences, Beijing 100049, China. Correspondence and requests for materials should be addressed to Z.F. (email: fanz@). NATURE COMMUNICATIONS | 6:7122 | DOI: 10.1038/ncomms8122 | /naturecommunications 1 2015 Macmillan Publishers Limited. All rig