The CCCTC-binding factor (CTCF)–forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma

Bin Zhang, Yajing Zhang, Xiaoping Zou, Anthony W.H. Chan, Rui Zhang, Kin Wah Lee, Hang Liu, Eunice Yuen Ting Lau, Nicole Pui Yu Ho, Paul B.S. Lai, Yue Sun Cheung, Ka Fai To, Hoi Kin Wong, Kwong Wai Choy, Wee-Keong Vincent Keng, Larry M.C. Chow, Kenrick K.Y. Chan, Alfred S. Cheng, Chi Bun Ko

Research output: Journal article publicationJournal articleAcademic researchpeer-review

13 Citations (Scopus)

Abstract

The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. 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 tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non-tumoural liver. Overexpression of CTCF was associated with shorter disease-free survival of patients. Short hairpin RNA (shRNA)-mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; these effects were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), the shelterin complex member telomerase repeat-binding factor 1, and forkhead box protein M1 (FOXM1). In contrast, 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)–polymerase chain reaction (PCR) analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo. Importantly, depletion of CTCF by shRNA significantly inhibited tumour 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. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Original languageEnglish
Pages (from-to)418-430
Number of pages13
JournalJournal of Pathology
Volume243
Issue number4
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • chromatin immunoprecipitation
  • CTCF
  • FOXM1
  • HCC
  • metastasis
  • TERT

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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