Marshall A D, Bailey C G, Champ K, Vellozzi M, O'Young P, Metierre C, Feng Y, Thoeng A, Richards A M, Schmitz U, Biro M, Jayasinghe R, Ding L, Anderson L, Mardis E R, Rasko J E J
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Oncogene. 2017 Jul 20;36(29):4100-4110. doi: 10.1038/onc.2017.25. Epub 2017 Mar 20.
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.
CTCF是一种单倍剂量不足的肿瘤抑制基因，在基因组结构和基因调控中具有多种正常功能。然而，CTCF单倍剂量不足促进癌症发展的机制尚不清楚。CTCF在子宫内膜癌中经常发生突变。在此，我们表明，大多数CTCF突变通过无义介导的突变转录本降解或功能丧失的错义突变有效地导致CTCF单倍剂量不足。相反，我们鉴定出一种反复出现的CTCF突变K365T，它改变了一个DNA结合残基，并作为一种功能获得性突变增强细胞存活。CTCF基因缺失主要发生在预后较差的浆液性亚型肿瘤中，这种基因缺失与总体生存率低有关。此外，我们已经表明，CTCF单倍剂量不足也发生在预后较差的子宫内膜透明细胞癌中，并且与子宫内膜癌的复发和转移有一定关联。使用靶向CTCF的shRNA来模拟CTCF单倍剂量不足，我们确定了CTCF在子宫内膜腺上皮细胞极性调节中的新作用。总体而言，我们确定了CTCF基因改变在子宫内膜癌中的两种新的促肿瘤作用（促进细胞存活和改变细胞极性）。
