title: Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation.
abstract: Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Berrios
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Megha
authors.initials: M
authors.lastname: Padi
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Keibler
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Donglim Esther
authors.initials: DE
authors.lastname: Park
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Vadim
authors.initials: V
authors.lastname: Molla
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Soo Mi
authors.identifier: http://orcid.org/0000-0003-3423-7965
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: John
authors.identifier: http://orcid.org/0000-0002-2702-5879
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James A
authors.identifier: http://orcid.org/0000-0002-0896-167X
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000502:physiology*; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D059965:Merkel cell polyomavirus; D055432:Metabolomics; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism / Q000821:virology*; D014162:Transfection
chemical_list: D000952:Antigens, Polyomavirus Transforming