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. © 2017 
The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on 
behalf of Pathological Society of Great Britain and Ireland.