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

doi:10.1016/j.molcel.2017.11.004

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

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

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 language	English
Pages (from-to)	731-744.e9
Journal	Molecular Cell
Volume	68
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2017.11.004
Publication status	Published - 2017 Nov 16

Bibliographical note

Funding 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.).

Publisher Copyright:
© 2017 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2017.11.004

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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

@article{2bfe431db223418f81a04604014f3e7b,

title = "Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene",

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.",

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

note = "Funding 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.). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = nov,

day = "16",

doi = "10.1016/j.molcel.2017.11.004",

language = "English",

volume = "68",

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journal = "Molecular Cell",

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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, JS, Davies, MA, Vakoc, CR, Hernando, E & Bernstein, E 2017, 'Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene', Molecular Cell, vol. 68, no. 4, pp. 731-744.e9. https://doi.org/10.1016/j.molcel.2017.11.004

TY - JOUR

T1 - Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

AU - Fontanals-Cirera, Barbara

AU - Hasson, Dan

AU - Vardabasso, Chiara

AU - Di Micco, Raffaella

AU - Agrawal, Praveen

AU - Chowdhury, Asif

AU - Gantz, Madeleine

AU - de Pablos-Aragoneses, Ana

AU - Morgenstern, Ari

AU - Wu, Pamela

AU - Filipescu, Dan

AU - Valle-Garcia, David

AU - Darvishian, Farbod

AU - Roe, Jae Seok

AU - Davies, Michael A.

AU - Vakoc, Christopher R.

AU - Hernando, Eva

AU - Bernstein, Emily

N1 - Funding 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.). Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/11/16

Y1 - 2017/11/16

N2 - 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.

AB - 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.

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Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Abstract

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