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.
Bibliographical noteFunding Information:
The authors thank Jay Bradner, Jian Jin, Iman Osman, Joanna Wysocka, Tomek Swigut, and Rana Moubarak for advice and reagents; Histopathology Core, Genomics Technology Center, and Proteomics Laboratory at NYU Langone Medical Center, supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center ; and Genomics Core Facility and Gayatri Panda at Icahn School of Medicine at Mount Sinai (ISMMS) and Alicia Alonso (Epigenomics Core at Weill Cornell Medicine) for sequencing assistance. The authors also thank the Functional Proteomics RPPA Core facility, supported by MD Anderson Cancer Center Support Grant P30CA016672 . This work was supported by Scientific Computing at ISMMS, Office of Research Infrastructure of the NIH to ISMMS ( S10OD018522 ), ISMMS Cancer Center Support Grant P30CA196521 , Leukemia and Lymphoma Society, Pershing Square Sohn Cancer Research Alliance, the Starr Cancer Consortium, and NIH/NCI R01CA174793 (J.-S.R. and C.R.V.); Dermatology Foundation (D.H.); Human Frontier Science Program postdoctoral fellowship and New York Stem Cell Foundation Druckenmiller postdoctoral fellowship (R.D.M.); R01CA155234 and R01CA163891 (E.H.); and Hirschl/Weill-Caulier Research Award, Melanoma Research Alliance, Harry J. Lloyd Charitable Trust, and NIH/NCI R01CA154683 (E.B.).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology