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Mol Cell. 2017 Nov 16;68(4):731-744.e9. doi: 10.1016/j.molcel.2017.11.004.

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene.

Author information

1
Department of Pathology and Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA.
2
Departments of Oncological Sciences and Dermatology, 1470 Madison Avenue, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Institute of Systems Genetics, New York University Langone Medical Center, New York, NY, USA.
4
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, USA.
5
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Pathology and Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA. Electronic address: eva.hernando-monge@nyumc.org.
7
Departments of Oncological Sciences and Dermatology, 1470 Madison Avenue, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: emily.bernstein@mssm.edu.

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.

KEYWORDS:

AMIGO2; BET; BET inhibition; BRD2; BRD4; PTK7; enhancers; melanoma

PMID:
29149598
PMCID:
PMC5993436
DOI:
10.1016/j.molcel.2017.11.004
[Indexed for MEDLINE]
Free PMC Article

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