The Journal of Pathology
The Journal of Pathology
5 years ago

CTCF-FOXM1 axis regulates tumor growth and metastasis in hepatocellular carcinoma

Hoi Kin Wong, Nicole Pui-Yu Ho, Eunice Yuen-Ting Lau, Alfred S. Cheng, Larry M.C. Chow, Kenrick K.Y. Chan, Xiaoping Zou, Hang Liu, Ka-Fai To, Paul B.S. Lai, Terence Kin-Wah Lee, Rui Zhang, Ben C.B. Ko, Bin Zhang, Kwong Wai Choy, Vincent W. Keng, Anthony W.H. Chan, Yue-Sun Cheung, Yajing Zhang
CCCTC-binding factor (CTCF) is a DNA-binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumor pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinoma (HCC) compared with non-tumoral liver. Overexpression of CTCF was associated with shorter disease-free survival of patients. Short hairpin RNA-mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; effects that were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), shelterin complex member (TRF1), and forkhead box protein M1 (FOXM1), whereas upregulation of CTCF was positively correlated with FOXM1 and TERT expression in clinical HCC biopsies. Depletion of CTCF resulted in reduced motility and invasiveness in HCC cells that could be reversed by ectopic expression of FOXM1, suggesting that FOXM1 is one of the important downstream effectors of CTCF in HCC. Reporter gene analysis suggested that depletion of CTCF is associated with reduced FOXM1 and TERT promoter activity. Chromatin immunoprecipitation (ChIP)-PCR analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo. Importantly, depletion of CTCF by shRNA significantly inhibited tumor progression and metastasis in HCC mouse models. Our work uncovered a novel functional role of CTCF in HCC pathogenesis, which suggests that targeting CTCF could be further explored as a potential therapeutic strategy for HCC.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/path.4976

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