The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor.
The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor.
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DOI：
10.1002/1878-0261.13101
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Brown KW
中科院分区：
文献类型：
--
作者：
Legge D;Li L;Moriarty W;Lee D;Szemes M;Zahed A;Panousopoulos L;Chung WY;Aghabi Y;Barratt J;Williams R;Pritchard-Jones K;Malik KTA;Oltean S;Brown KW
肾母细胞瘤（Wilms tumor， WT）是一种胚胎性肾癌，已被广泛地描述为遗传和表观遗传改变，但一部分WTs仍然缺乏可识别的异常。为了揭示对WT发病至关重要的DNA甲基化变化，我们比较了两种WT细胞系胎儿肾脏的表观基因组，过滤我们的结果以去除常见的癌症相关表观遗传变化，并富集参与早期肾脏发育的基因。研究发现了4个高甲基化基因，其中ESRP2（上皮剪接调节蛋白2）是最有希望进一步研究的基因。在WT中，ESRP2通常被DNA甲基化抑制，这发生在WT发展的早期（在肾源性rest中）。通过DNA甲基转移酶抑制，WT细胞系中ESRP2的表达被重新激活。当ESRP2在WT细胞系中过表达时，在体外可抑制细胞增殖，在体内可抑制裸鼠原位异种移植物的肿瘤生长。表达ESRP2的WT细胞系的RNA - seq鉴定出几个新的剪接靶点。我们提出了一个模型，其中表观遗传失活的ESRP2破坏了早期肾脏发育过程中间质到上皮的转变，从而产生WT。ESRP2调节了对肾脏发育过程中间质到上皮转变（MET）至关重要的选择性剪接事件。我们发现，在Wilms肿瘤中，ESRP2通常在癌变早期被DNA甲基化灭活。我们认为ESRP2的表观遗传失活破坏了MET过程中选择性剪接的调节。紊乱的MET反过来导致未分化的胎儿肾细胞持续存在，并可能发展为肿瘤。
Wilms tumour (WT), an embryonal kidney cancer, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of foetal kidney with two WT cell lines, filtering our results to remove common cancer‐associated epigenetic changes and to enrich for genes involved in early kidney development. This identified four hypermethylated genes, of which ESRP2 (epithelial splicing regulatory protein 2) was the most promising for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this occurred early in WT development (in nephrogenic rests). ESRP2 expression was reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it inhibited cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA‐seq of the ESRP2‐expressing WT cell lines identified several novel splicing targets. We propose a model in which epigenetic inactivation of ESRP2 disrupts the mesenchymal to epithelial transition in early kidney development to generate WT. ESRP2 regulates alternative splicing events that are critical for the mesenchymal to epithelial transition (MET) that occurs during kidney development. We show that in Wilms tumour, ESRP2 is commonly inactivated by DNA methylation at an early stage of carcinogenesis. We propose that epigenetic inactivation of ESRP2 disrupts the regulation of alternative splicing during MET. Disrupted MET leads in turn to persistence of undifferentiated foetal kidney cells that may progress to a tumour.
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影响因子：
1.9
作者：
Brown, Keith W.;Charles, Adrian;Malik, Karim
通讯作者：
Malik, Karim
影响因子：
8
作者：
Mizutani A;Koinuma D;Seimiya H;Miyazono K
通讯作者：
Miyazono K
DOI：
10.1073/pnas.1214394109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Di Modugno, Francesca;Iapicca, Pierluigi;Nistico, Paola
通讯作者：
Nistico, Paola
影响因子：
5.3
作者：
Dittmar, Kimberly A.;Jiang, Peng;Carstens, Russell P.
通讯作者：
Carstens, Russell P.
影响因子：
30.8
作者：
BARDEESY, N;FALKOFF, D;PELLETIER, J
通讯作者：
PELLETIER, J