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Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response

Park, Donglim Esther ; Cheng, Jingwei ; Berrios, Christian ; Montero, Joan ; Cortés-Cros, Marta ; Ferretti, Stéphane ; Arora, Reety ; Tillgren, Michelle L. ; Gokhale, Prafulla C. ; DeCaprio, James A.

Proceedings of the National Academy of Sciences - PNAS, 2019-01, Vol.116 (3), p.1027-1032 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response
Autor: Park, Donglim Esther ; Cheng, Jingwei ; Berrios, Christian ; Montero, Joan ; Cortés-Cros, Marta ; Ferretti, Stéphane ; Arora, Reety ; Tillgren, Michelle L. ; Gokhale, Prafulla C. ; DeCaprio, James A.
Assuntos: Activation ; Antigen T (large) ; Apoptosis ; Biological Sciences ; Cancer ; Carcinoma ; Carcinoma, Merkel Cell - genetics ; Carcinoma, Merkel Cell - metabolism ; Carcinoma, Merkel Cell - pathology ; Carcinoma, Merkel Cell - virology ; Cell Cycle Proteins ; Chromatin ; Depletion ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Gene expression ; Gene sequencing ; Genes ; Homology ; Humans ; Inhibitors ; MDM2 protein ; Merkel cell polyomavirus - genetics ; Merkel cell polyomavirus - metabolism ; Mutation ; Myc protein ; Neuroendocrine tumors ; Nuclear Proteins - antagonists & inhibitors ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; p53 Protein ; Polyomavirus Infections - genetics ; Polyomavirus Infections - metabolism ; Polyomavirus Infections - pathology ; Proteins ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2 - genetics ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Retinoblastoma Binding Proteins - genetics ; Retinoblastoma Binding Proteins - metabolism ; Ribonucleic acid ; RNA ; Rodents ; Skin ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumor Virus Infections - genetics ; Tumor Virus Infections - metabolism ; Tumor Virus Infections - pathology ; Tumors ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Viruses ; Xenografts ; Xenotransplantation
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2019-01, Vol.116 (3), p.1027-1032
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Edited by Carol Prives, Columbia University, New York, NY, and approved December 3, 2018 (received for review November 2, 2018)
Author contributions: D.E.P., M.C.-C., P.C.G., and J.A.D. designed research; D.E.P., J.C., J.M., and M.L.T. performed research; J.C., C.B., M.C.-C., S.F., and R.A. contributed new reagents/analytic tools; D.E.P., J.M., and M.L.T. analyzed data; and D.E.P. and J.A.D. wrote the paper.
Descrição: Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST–MYCL–EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST–MYCL–EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response

Park, Donglim Esther ; Cheng, Jingwei ; Berrios, Christian ; Montero, Joan ; Cortés-Cros, Marta ; Ferretti, Stéphane ; Arora, Reety ; Tillgren, Michelle L. ; Gokhale, Prafulla C. ; DeCaprio, James A.

United States: National Academy of Sciences

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