Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

被引：96

作者：

Fontanals-Cirera, Barbara ^{[1
,2
]}

Hasson, Dan ^{[3
,4
]}

Vardabasso, Chiara ^{[3
,4
]}

Di Micco, Raffaella ^{[1
,2
]}

Agrawal, Praveen ^{[1
,2
]}

Chowdhury, Asif ^{[3
,4
]}

Gantz, Madeleine ^{[3
,4
]}

de Pablos-Aragoneses, Ana ^{[1
,2
]}

Morgenstern, Ari ^{[1
,2
]}

Wu, Pamela ^{[5
]}

Filipescu, Dan ^{[3
,4
]}

Valle-Garcia, David ^{[3
,4
]}

Darvishian, Farbod ^{[1
,2
]}

Roe, Jae-Seok ^{[6
]}

Davies, Michael A. ^{[7
]}

Vakoc, Christopher R. ^{[6
]}

Hernando, Eva ^{[1
,2
]}

Bernstein, Emily ^{[3
,4
]}

机构：

[1] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10003 USA

[2] NYU, Langone Med Ctr, Interdisciplinary Melanoma Cooperat Grp, New York, NY 10003 USA

[3] Icahn Sch Med Mt Sinai, Dept Oncol Sci, 1470 Madison Ave, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Dept Dermatol, 1470 Madison Ave, New York, NY 10029 USA

[5] NYU, Langone Med Ctr, Inst Syst Genet, New York, NY USA

[6] Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

来源：

MOLECULAR CELL | 2017年 / 68卷 / 04期

关键词：

KINASE; 7; PTK7; TRANSCRIPTION FACTORS; GASTRIC ADENOCARCINOMA; BROMODOMAIN INHIBITION; CHROMATIN ARCHITECTURE; SELECTIVE-INHIBITION; INTEGRATIVE ANALYSIS; MALIGNANT-MELANOMA; SUPER-ENHANCERS; CELL IDENTITY;

D O I：

10.1016/j.molcel.2017.11.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：731 / +

页数：23

共 82 条

[1] Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice [J].

Adam, Rene C. ;

Yang, Hanseul ;

Rockowitz, Shira ;

Larsen, Samantha B. ;

Nikolova, Maria ;

Oristian, Daniel S. ;

Polak, Lisa ;

Kadaja, Meelis ;

Asare, Amma ;

Zheng, Deyou ;

Fuchs, Elaine .

NATURE, 2015, 521 (7552) :366-+

[2] A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis [J].

Agrawal, Praveen ;

Fontanals-Cirera, Barbara ;

Sokolova, Elena ;

Jacob, Samson ;

Vaiana, Christopher A. ;

Argibay, Diana ;

Davalos, Veronica ;

McDermott, Meagan ;

Nayak, Shruti ;

Darvishian, Farbod ;

Castillo, Mireia ;

Ueberheide, Beatrix ;

Osman, Iman ;

Fenyo, David ;

Mahal, Lara K. ;

Hernando, Eva .

CANCER CELL, 2017, 31 (06) :804-+

[3] Genomic Classification of Cutaneous Melanoma [J].

Akbani, Rehan ;

Akdemir, Kadir C. ;

Aksoy, B. Arman ;

Albert, Monique ;

Ally, Adrian ;

Amin, Samirkumar B. ;

Arachchi, Harindra ;

Arora, Arshi ;

Auman, J. Todd ;

Ayala, Brenda ;

Baboud, Julien ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barnabas, Nandita ;

Bartlett, John ;

Bartlett, Pam ;

Bastian, Boris C. ;

Baylin, Stephen B. ;

Behera, Madhusmita ;

Belyaev, Dmitry ;

Benz, Christopher ;

Bernard, Brady ;

Beroukhim, Rameen ;

Bir, Natalie ;

Black, Aaron D. ;

Bodenheimer, Tom ;

Boice, Lori ;

Boland, Genevieve M. ;

Bono, Riccardo ;

Bootwalla, Moiz S. ;

Bosenberg, Marcus ;

Bowen, Jay ;

Bowlby, Reanne ;

Bristow, Christopher A. ;

Brockway-Lunardi, Laura ;

Brooks, Denise ;

Brzezinski, Jakub ;

Bshara, Wiam ;

Buda, Elizabeth ;

Burns, William R. ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Calderone, Tiffany ;

Cappellini, Giancarlo Antonini ;

Carter, Candace ;

Carter, Scott L. ;

Cherney, Lynn ;

Cherniack, Andrew D. ;

Chevalier, Aaron ;

Chin, Lynda .

CELL, 2015, 161 (07) :1681-1696

[4] Epigenomic Enhancer Profiling Defines a Signature of Colon Cancer [J].

Akhtar-Zaidi, Batool ;

Lari, Richard Cowper-Sal ;

Corradin, Olivia ;

Saiakhova, Alina ;

Bartels, Cynthia F. ;

Balasubramanian, Dheepa ;

Myeroff, Lois ;

Lutterbaugh, James ;

Jarrar, Awad ;

Kalady, Matthew F. ;

Willis, Joseph ;

Moore, Jason H. ;

Tesar, Paul J. ;

Laframboise, Thomas ;

Markowitz, Sanford ;

Lupien, Mathieu ;

Scacheri, Peter C. .

SCIENCE, 2012, 336 (6082) :736-739

[5] Genome-wide localization of small molecules [J].

Anders, Lars ;

Guenther, Matthew G. ;

Qi, Jun ;

Fan, Zi Peng ;

Marineau, Jason J. ;

Rahl, Peter B. ;

Loven, Jakob ;

Sigova, Alla A. ;

Smith, William B. ;

Lee, Tong Ihn ;

Bradner, James E. ;

Young, Richard A. .

NATURE BIOTECHNOLOGY, 2014, 32 (01) :92-+

[6] Novel anticancer compounds induce apoptosis in melanoma cells [J].

Bhat, Uppoor G. ;

Zipfel, Patricia A. ;

Tyler, Douglas S. ;

Gartel, Andrei L. .

CELL CYCLE, 2008, 7 (12) :1851-1855

[7]

Buenrostro Jason D, 2015, Curr Protoc Mol Biol, V109, DOI 10.1002/0471142727.mb2129s109

[8]

Buenrostro JD, 2013, NAT METHODS, V10, P1213, DOI [10.1038/NMETH.2688, 10.1038/nmeth.2688]

[9] The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset [J].

Ceol, Craig J. ;

Houvras, Yariv ;

Jane-Valbuena, Judit ;

Bilodeau, Steve ;

Orlando, David A. ;

Battisti, Valentine ;

Fritsch, Lauriane ;

Lin, William M. ;

Hollmann, Travis J. ;

Ferre, Fabrizio ;

Bourque, Caitlin ;

Burke, Christopher J. ;

Turner, Laura ;

Uong, Audrey ;

Johnson, Laura A. ;

Beroukhim, Rameen ;

Mermel, Craig H. ;

Loda, Massimo ;

Ait-Si-Ali, Slimane ;

Garraway, Levi A. ;

Young, Richard A. ;

Zon, Leonard I. .

NATURE, 2011, 471 (7339) :513-+

[10] Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

← 1 2 3 4 5 6 7 8 9 →