C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling

Pingping Zhu, Yanying Wang, Ying Du, Lei He, Guanling Huang, Geng Zhang, Xinlong Yan and Zusen Fan ()
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Pingping Zhu: School of Life Sciences, University of Science and Technology of China
Yanying Wang: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
Ying Du: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
Lei He: PLA General Hospital
Guanling Huang: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
Geng Zhang: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
Xinlong Yan: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
Zusen Fan: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8122

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