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致癌性表皮生长因子受体抑制TET1 DNA去甲基化酶以诱导癌细胞中肿瘤抑制基因沉默。

Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells.

作者信息

Forloni Matteo, Gupta Romi, Nagarajan Arvindhan, Sun Li-Sha, Dong Yuying, Pirazzoli Valentina, Toki Maria, Wurtz Anna, Melnick Mary Ann, Kobayashi Susumu, Homer Robert J, Rimm David L, Gettinger Scott J, Politi Katerina, Dogra Shaillay Kumar, Wajapeyee Narendra

机构信息

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.

Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.

出版信息

Cell Rep. 2016 Jul 12;16(2):457-471. doi: 10.1016/j.celrep.2016.05.087. Epub 2016 Jun 23.

DOI:10.1016/j.celrep.2016.05.087
PMID:27346347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4945411/
Abstract

Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.

摘要

癌基因诱导的肿瘤抑制因子DNA甲基化介导的转录沉默在癌症中频繁发生，但其在肿瘤发生过程中这种沉默的机制和功能作用尚未完全阐明。在此，我们表明致癌性表皮生长因子受体（EGFR）通过C/EBPα转录因子抑制DNA去甲基化酶TET癌基因家族成员1（TET1），从而诱导肺腺癌和胶质母细胞瘤中多个不相关的肿瘤抑制因子沉默。致癌性EGFR抑制后，TET1与肿瘤抑制因子启动子结合，并通过活性DNA去甲基化诱导它们重新表达。TET1的异位表达有力地抑制肺癌和胶质母细胞瘤的肿瘤生长，而TET1敲低赋予肺癌细胞对EGFR抑制剂的抗性。在大多数病例中，肺癌样本显示TET1表达降低或TET1定位于细胞质。总体而言，这些结果确定了致癌性EGFR诱导的肿瘤抑制因子DNA甲基化介导的转录沉默的保守途径，这可能对致癌性EGFR介导的肺癌和胶质母细胞瘤具有治疗益处。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/0cb92c5d3a22/nihms792074f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/552bfd3c4993/nihms792074f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/df8d5f9e4bf4/nihms792074f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/4fe668a3d9cf/nihms792074f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/54acdbb13680/nihms792074f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/bff5f0c4e431/nihms792074f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/0c3d9182f98d/nihms792074f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/0cb92c5d3a22/nihms792074f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/552bfd3c4993/nihms792074f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/df8d5f9e4bf4/nihms792074f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/4fe668a3d9cf/nihms792074f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/54acdbb13680/nihms792074f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/bff5f0c4e431/nihms792074f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/0c3d9182f98d/nihms792074f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/564f/4945411/0cb92c5d3a22/nihms792074f7.jpg

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