The tumor suppressor role of CTCF

Abstract

CTCF is an evolutionary conserved and ubiquitously expressed protein that binds thousands of sites in the human genome. Ectopic expression of CTCF in various normal and tumoral human cell lines inhibits cell division and clonogenicity, with the consequence to consider CTCF a potential tumor-suppressor factor. In this review article, we focused on the molecular mechanisms engaged by CTCF to modulate the expression of several key-regulators of differentiation, cellular senescence, cell cycle control and progression, whose expression is frequently altered in tumors. Moreover, we discussed common features of CTCF at each tumor-related DNA-binding sequence, such as protein-partners, post-translational modifications, and distinctive epigenetic marks establishment. The investigation of the molecular mechanisms engaged by CTCF to modulate tumor-related genes emphasizes the cell-type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell-type features as DNA methylation, BORIS-binding and post-translational modifications as PARYlation.

The Promoter Methylation Status and mRNA Expression Levels ofCTCFandSIRT6in Sporadic Breast Cancer

“…Among its multiple functions, a growing amount of evidence implicates CTCF in the epigenetic regulation of genes responsible for the control of the cell cycle, and its misregulation can lead to aberrant epigenetic silencing of genes involved in cancer development (Recillas-Targa et al, 2011). CTCF was also recognized as a potential tumor suppressor gene in breast cancer (Filippova et al, 1998(Filippova et al, , 2002Rasko et al, 2001;Fiorentino and Giordano, 2012), and CTCF suppresses breast cancer growth (Tiffen et al, 2013). To our knowledge, all publications currently available mainly describe that loss of CTCF binding due to hypermethylation leads to subsequent silencing of tumor suppressor gene loci, including BRCA1 (Butcher et al, 2004), retinoblastoma (Rb) (De la Rosa-Velazquez et al, 2007), p16(INK4a) (Witcher andEmerson, 2009), p53 (Soto-Reyes andRecillas-Targa, 2010), and retinoic acid receptor responder 1 (RARRES1) (Peng et al, 2012).…”

“…Identification of these genes has helped begin to elucidate the molecular pathogenesis of breast carcinoma, as it reveals intracellular pathways that are altered that likely contribute to oncogenesis. CCCTC-binding factor (CTCF) and sirtuin 6 (SIRT6) have currently been suggested to function as a potential tumor suppressor in breast cancer (Fiorentino and Giordano, 2012;Sebastian et al, 2012) and CpG islands mapped to the promoter regions of CTCF and SIRT6 [chr16:67595310-67644735 and chr19:4182537-4183596, respectively, UCSC assembly: Feb. 2009 (GRCh37/ hg19)]. Based on a PubMed search, we found that CTCF and SIRT6 had not been analyzed in breast cancers by other studies previously.…”

CTCF (CCCTC-binding factor (zinc finger protein))

“…There is evidence for a tumor-suppressor role of CTCF (reviewed in Fiorentino and Giordano, 2012). LOH of CTCF was described in many cancers together with potential tumor suppressor genes (TSG), including ECad, since it is part of a larger deletion (Cancer Chromosomes; Sanger institute).…”

Integrating role of T antigen, Rb2/p130, CTCF and BORIS in mediating non-canonical endoplasmic reticulum-dependent death pathways triggered by chronic ER stress in mouse medulloblastoma

“…Remarkably, it has been indicated that both BORIS and CTCF are overexpressed in a variety of human cancers. 7 Interestingly, we recently reported that CTCF and BORIS directly regulate Rb2/p130 gene transcription in lung cancer and suggested a novel role for Rb2/p130 in the mechanisms used by cancer cells in evading senescence and apoptosis and promoting accelerated cell proliferation. 8 Caspase-12 is a member of the caspase family of intracellular cysteine proteases and was first identified in mice.…”

“…6 CTCF possesses many DNA-regulation functions, including acting as a chromatin insulator, enhancer blocker, transcription activator and nuclear organizer. 7 Presently, how CTCF is able to accomplish all of these functions is still unknown. Current literature suggests DNA binding competition between CTCF and BORIS, a CTCF paralog normally present only in male germ cells, to elicit opposite changes in gene expression.…”