Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis
Jingwei Cheng,Donglim Esther Park,Christian Berrios,Elizabeth A. White,Reety Arora,Rosa Yoon,Timothy Branigan,Tengfei Xiao,Thomas Westerling,Thomas Westerling,Alexander J. Federation,Rhamy Zeid,Benjamin J. Strober,Selene K. Swanson,Laurence Florens,James E. Bradner,James E. Bradner,Myles Brown,Peter M. Howley,Megha Padi,Michael P. Washburn,Michael P. Washburn,James A. DeCaprio,James A. DeCaprio +23 more
TLDR
It is demonstrated that ST can activate gene expression in a EP400 and MYCL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.Abstract:
Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MYCL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MYCL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MYCL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MYCL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MYCL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.read more
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The biology and treatment of Merkel cell carcinoma: current understanding and research priorities
Paul W. Harms,Kelly L. Harms,Patrick S. Moore,James A. DeCaprio,Paul Nghiem,Michael K K Wong,Isaac Brownell +6 more
TL;DR: The availability of immune checkpoint inhibition has improved the outcomes of a subset of patients with MCC, although many unmet needs continue to exist, according to this Consensus Statement.
Journal ArticleDOI
The MYC oncogene - the grand orchestrator of cancer growth and immune evasion.
Renumathy Dhanasekaran,Anja Deutzmann,Wadie D. Mahauad-Fernandez,Aida S. Hansen,Arvin M. Gouw,Dean W. Felsher +5 more
TL;DR: In this article, the authors discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer, and propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
Journal ArticleDOI
Virus DNA Replication and the Host DNA Damage Response.
TL;DR: Consequences for viral replication and host genome integrity during the dynamic interactions between virus and host are highlighted.
Journal ArticleDOI
The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy
Todd C. Knepper,Meagan Montesion,Jeffery S. Russell,Ethan Sokol,Garrett M. Frampton,Vincent A. Miller,Lee A. Albacker,Howard L. McLeod,Zeynep Eroglu,Nikhil I. Khushalani,Vernon K. Sondak,Jane L. Messina,Michael J. Schell,James A. DeCaprio,Kenneth Y. Tsai,Andrew S. Brohl +15 more
TL;DR: The largest genomics study in MCC to date is performed to characterize the molecular landscape and demonstrate clinicogenomic associates of immunotherapy response and provide a comprehensive genomic landscape of MCC.
Journal ArticleDOI
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Donglim Esther Park,Jingwei Cheng,Christian Berrios,Joan Montero,Marta Cortes-Cros,Stephane Ferretti,Reety Arora,Reety Arora,Michelle Tillgren,Prafulla C. Gokhale,James A. DeCaprio +10 more
TL;DR: The mechanism behind MCV control of p53 in MCC is uncovered and the utility of targeting MDM2 and MDM4 combinatorially in p53 wild-type tumors is demonstrated.
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