CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer

CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.3390/ijms19123832
Journal or Publication Title: International Journal of Molecular Sciences
Volume: 19
Number: 12
Page Range: p. 3832
Date: 2018
Divisions: Gene and Stem Cell Therapy
Depositing User: General Admin
Identification Number: 10.3390/ijms19123832
ISSN: 1422-0067
Date Deposited: 04 Jan 2021 23:27

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 as well as 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.

Bailey, Charles
Metierre, Cynthia
Feng, Yue
Baidya, Kinsha
Filippova, Galina
Loukinov, Dmitri
Lobanenkov, Victor
Semaan, Crystal
Rasko, John
Last Modified: 04 Jan 2021 23:27
URI: https://eprints.centenary.org.au/id/eprint/577

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