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

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

80 Scopus citations

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 (US)
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
State	Published - Nov 16 2017
Externally published	Yes

Keywords

AMIGO2
BET
BET inhibition
BRD2
BRD4
PTK7
enhancers
melanoma

ASJC Scopus subject areas

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

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

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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.",

keywords = "AMIGO2, BET, BET inhibition, BRD2, BRD4, PTK7, enhancers, melanoma",

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",

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

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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

PY - 2017/11/16

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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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KW - BET

KW - BET inhibition

KW - BRD2

KW - BRD4

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KW - enhancers

KW - melanoma

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Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Abstract

Keywords

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