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

Abstract

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.

Up‐regulation of SNHG16 induced by CTCF accelerates cardiac hypertrophy by targeting miR‐182‐5p/IGF1 axis

“…Further, CTCF has been researched and revealed to serve as an oncogene in some cancers, such as prostate cancer (Shan et al, 2019) and hepatocellular carcinoma (Zhang et al, 2017). Besides, its effect of being able to activating gene transcription has been validated in some cases (Beishline et al, 2017; Sekiya et al, 2019).…”

Expression of CCCTC‐binding factor (CTCF) is linked to poor prognosis in prostate cancer

“…A tumor-promoting role of CTCF is also supported by studies in other cancer types. For example, CTCF upregulation was linked to advanced or metastatic disease and poor prognosis in hepatocellular carcinoma and ovarian cancers (Zhang et al, 2017;Zhao et al, 2017). CTCF has a multifunctional role enabling chromatin looping for interactions between distal enhancers and proximal promoters.…”

“…Thus, it is not surprising that deregulation of CTCF has been observed in many human cancer types. For example, overexpression of CTCF has been reported to occur in breast cancer (Docquier et al, 2005), cervical cancer (Velazquez-Hernandez et al, 2015), ovarian cancer (Zhao et al, 2017), and hepatocellular carcinoma (Zhang et al, 2017), and has been linked to adverse tumor features in some of them (Zhang et al, 2017;Zhao et al, 2017). Little is known about the clinical impact of CTCF expression in prostate cancer.…”

One protein to rule them all: The role of CCCTC-binding factor in shaping human genome in health and disease

“…The CTCF mediated high-order spatial chromatin organization may contribute to the somatic co-mutations of certain cancer genes [109]. CTCF upregulation has been shown to decrease disease-free survival of patients affected with hepatocellular carcinoma by enhancing the expression of forkhead box protein M1 and telomerase reverse transcriptase [110].…”