Fontanals-Cirera, B., Hasson, D., Vardabasso, C., Di Micco, R., Agrawal, P., Chowdhury, A., Gantz, M., de Pablos-Aragoneses, A., Morgenstern, A., Wu, P., Filipescu, D., Valle-Garcia, D., Darvishian, F., Roe, J. S., Davies, M. A., Vakoc, C. R., Hernando, E., Bernstein, E. (November 2017) Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. Mol Cell, 68 (4). 731-744.e9. ISSN 1097-2765
Abstract
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Amigo2 Bet BET inhibition Brd2 Brd4 Ptk7 enhancers melanoma |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4 diseases & disorders > cancer > cancer types > melanomas |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 16 November 2017 |
| Date Deposited: | 01 Dec 2017 20:56 |
| Last Modified: | 06 Jul 2021 19:22 |
| PMCID: | PMC5993436 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35678 |
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