Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A. Davies, Christopher R. Vakoc, Eva Hernando, Emily Bernstein

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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. BET proteins play a central role in melanoma maintenance. By interrogating the effects of BET inhibition on melanoma transcriptional programs and regulatory elements, Fontanals-Cirera and Hasson et al. identified the transmembrane protein AMIGO2 as a survival factor whose expression is regulated by BET- and FOSL/TEAD-bound DNA regulatory elements.

Original languageEnglish
Pages (from-to)731-744.e9
JournalMolecular Cell
Volume68
Issue number4
DOIs
Publication statusPublished - 2017 Nov 16

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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. (2017). Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. Molecular Cell, 68(4), 731-744.e9. https://doi.org/10.1016/j.molcel.2017.11.004