CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic

Marshall, Amy D.; Bailey, Charles G.; Champ, K; Vellozzi, Melissa; O’Young, Patrick; Metierre, Cynthia; Feng, Yongmei; Thoeng, Annora; Richards, Anthony; Schmitz, Ulf; Biro, Maté; Jayasinghe, Reyka G.; Li, Ding; Anderson, Lyndal; Mardis, Elaine R.; Rasko, John E.J.

doi:10.1038/onc.2017.25

Cited by 50 publications

(65 citation statements)

References 48 publications

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“…These data and our previous studies indicated that CTCF dosage is critical for its tumour suppressive functions [25], [32], however CTCF haploinsufficiency has not been definitively modelled in vitro. To address this, we used CRISPR/Cas9-directed genome editing to induce genetic lesions in K562 cells (Supplementary Figure 1A), which we previously verified to contain wild type CTCF alleles using Sanger sequencing [25].…”

Section: Resultscontrasting

confidence: 43%

“…Genetic lesions in CTCF, whether heterozygous deletion, nonsense, frameshift or even missense zinc finger (ZF) mutations, can all result in CTCF haploinsufficiency. In endometrial cancer, CTCF mRNA transcripts expressed from alleles containing nonsense or frameshift mutations are subjected to nonsense-mediated decay [30], [32]. Somatic missense mutations in residues critical for CTCF ZF binding to DNA can result in selective loss of binding to some CTCF target sites, but not all [26], indicating the functional implications of incomplete loss of CTCF binding in cancer is unclear.…”

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confidence: 99%

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CTCF Expression Is Essential for Somatic Cell Viability and Protection against Cancer

Bailey¹,

Metierre²,

Feng³

et al. 2018

Preprint

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CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown, functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing and examined the growth and development of heterozygous Ctcf (Ctcf+/-) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/- MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression and decreased survival after apoptotic insult compared to wild type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/- MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.

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Section: Resultscontrasting

confidence: 43%

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confidence: 99%

CTCF Expression Is Essential for Somatic Cell Viability and Protection against Cancer

Bailey¹,

Metierre²,

Feng³

et al. 2018

Preprint

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“…All of those transcription factors (except CEBPA) are known to be expressed in the glands of the human endometrium. CTCF can function as a transcriptional activator, a repressor, or an insulator and regulates cell polarity of the GE (55). FOSL2 is a component of the activator protein 1 transcription factor complex and regulates cell proliferation, differentiation, and transformation, but its role in uterine glands is not known.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

et al. 2019

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The pioneer forkhead box (FOX)A2 transcription factor is specifically expressed in the glands of the uterus, which are central to endometrial function and fertility. In mice, FOXA2 is a critical regulator of uterine gland development in the neonate and gland function in the adult. An integrative approach was used here to define the FOXA2 cistrome in the human endometrium. Genome‐wide mapping of FOXA2 binding intervals by chromatin immunoprecipitation sequencing was performed using proliferative (P)‐ and midsecretory (MS)‐phase endometrium and integrated with the transcriptome determined by RNA sequencing. Distinctive FOXA2 binding intervals, enriched for different transcription factor binding site motifs, were detected in the P and MS endometrium. Pathway analysis revealed different biologic processes regulated by genes with FOXA2 binding intervals in the P and MS endometrium. Thus, FOXA2 is postulated to regulate gene expression in concert with other transcription factors and impact uterine gland development and function in a cycle phase–dependent manner. Analyses also identified potential FOXA2‐regulated genes that influence uterine receptivity, blastocyst implantation, and stromal cell decidualization, which are key events in pregnancy establishment.—Kelleher, A. M., Behura, S. K., Burns, G. W., Young, S. L., DeMayo, F. J., Spencer, T. E. Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium. FASEB J. 33, 8543–8554 (2019). http://www.fasebj.org

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“…Indeed, frequent mutations of CTCF motifs in the vicinity of oncogenes have been reported in colorectal, liver and esophageal cancer (58, 59). Furthermore, the CTCF protein and its associated boundary factor cohesion are both subject to recurrent mutation in multiple tumor types (60–63). CTCF haploinsufficiency has also been shown to promote tumor formation in mice (64).…”

Section: Epigenetic Plasticity: Dna Methylation and Disruption Of Oncmentioning

confidence: 99%

Epigenetic plasticity and the hallmarks of cancer

Flavahan

Gaskell

Bernstein

2017

Science

970

804

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Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states, while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or ‘plastic’ states may allow stochastic oncogene activation or non-physiologic cell fate transitions. While many stochastic events will be inconsequential ‘passengers’, some will confer fitness and be selected as ‘drivers’. We review the broad roles played by epigenetic aberrations in tumor initiation and evolution, and their potential to give rise to all classic hallmarks of cancer.

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CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic

Cited by 50 publications

References 48 publications

CTCF Expression Is Essential for Somatic Cell Viability and Protection against Cancer

CTCF Expression Is Essential for Somatic Cell Viability and Protection against Cancer

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

Epigenetic plasticity and the hallmarks of cancer

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