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Oncogene. 2017 Jul 20;36(29):4100-4110. doi: 10.1038/onc.2017.25. Epub 2017 Mar 20.

CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic.

Author information

1
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.
2
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
3
Gynaecological Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
4
Cell Motility and Mechanobiology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
5
Cancer Genomics, McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA.
6
Division of Oncology, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
7
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
8
Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Abstract

CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival. CTCF genetic deletion occurs predominantly in poor prognosis serous subtype tumours, and this genetic deletion is associated with poor overall survival. In addition, we have shown that CTCF haploinsufficiency also occurs in poor prognosis endometrial clear cell carcinomas and has some association with endometrial cancer relapse and metastasis. Using shRNA targeting CTCF to recapitulate CTCF haploinsufficiency, we have identified a novel role for CTCF in the regulation of cellular polarity of endometrial glandular epithelium. Overall, we have identified two novel pro-tumorigenic roles (promoting cell survival and altering cell polarity) for genetic alterations of CTCF in endometrial cancer.

PMID:
28319062
PMCID:
PMC5519450
DOI:
10.1038/onc.2017.25
[Indexed for MEDLINE]
Free PMC Article

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