title: Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma.
abstract: Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vardabasso
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gaspar-Maia
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hasson
authors.affiliation: Center for Integrated Protein Science Munich and Department of Molecular Biology, Adolf-Butenandt Institute, Ludwig-Maximilians University, 80336 Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pünzeler
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Molecular Genetics Department, Institute for Cellular Physiology, National Autonomous University of Mexico, 04510 Mexico City, Mexico.
authors.forename: David
authors.initials: D
authors.lastname: Valle-Garcia
authors.affiliation: Center for Integrated Protein Science Munich and Department of Molecular Biology, Adolf-Butenandt Institute, Ludwig-Maximilians University, 80336 Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Straub
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Keilhauer
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Strub
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Taniya
authors.initials: T
authors.lastname: Panda
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chi-Yeh
authors.initials: CY
authors.lastname: Chung
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Yao
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Pathology and Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
authors.affiliation: Department of Pathology and Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fontanals-Cirera
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Department of Pathology and Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.affiliation: Center for Integrated Protein Science Munich and Department of Molecular Biology, Adolf-Butenandt Institute, Ludwig-Maximilians University, 80336 Munich, Germany. Electronic address: sandra.hake@med.uni-muenchen.de.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Hake
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: emily.bernstein@mssm.edu.
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D017423:Sequence Analysis, RNA; D014157:Transcription Factors; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D050687:E2F1 Transcription Factor; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C493753:E2F1 protein, human; C077020:histone H2A.F-Z