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| Status |
Public on Jun 23, 2016 |
| Title |
Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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 is 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 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 via 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 a majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors, which may have therapeutic benefit for oncogenic EGFR-mediated lung cancers and glioblastomas.
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| Overall design |
HCC827-Del (EGFR L747-S752) and HCC827-Del-TM (EGFR L747-S752/T790M) cell lines were treated with Decitibine (2.5 μM) and Vorinostat (1μM) or as a control cells that were treated with DMSO for 72 hrs. Expression profiling was performed using 3 biological replicates for each condition for a total of 12 samples analyzed.
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| Contributor(s) |
Forloni M, Gupta R, Dogra S, Nagarajan A, Wajapeyee N |
| Citation(s) |
27346347 |
| Submission date |
Jul 12, 2012 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Narendra Wajapeyee |
| E-mail(s) |
nwajapey@uab.edu
|
| Phone |
205-934-5331
|
| Organization name |
University of Alabama at Birmingham
|
| Department |
Department of Biochemistry and Molecular Genetics
|
| Street address |
720 20th Street South, Kaul 540A
|
| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35233 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (12)
|
| GSM960266 |
HCC827-Del+Decitabine+Vorinostat replicate 1 |
| GSM960267 |
HCC827-Del+Decitabine+Vorinostat replicate 2 |
| GSM960268 |
HCC827-Del+Decitabine+Vorinostat replicate 3 |
| GSM960269 |
HCC827-Del-TM replicate 1 |
| GSM960270 |
HCC827-Del-TM replicate 2 |
| GSM960271 |
HCC827-Del-TM replicate 3 |
| GSM960272 |
HCC827-Del-TM+Decitabine+Vorinostat replicate 1 |
| GSM960273 |
HCC827-Del-TM+Decitabine+Vorinostat replicate 2 |
| GSM960274 |
HCC827-Del-TM+Decitabine+Vorinostat replicate 3 |
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| Relations |
| BioProject |
PRJNA170509 |
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