title: HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.
abstract: Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.
authors.affiliation: Department of Pathology, Pediatric Brain Tumor Foundation Institute and Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Stephen
authors.initials: S
authors.lastname: Cook
authors.forename: Bo
authors.initials: B
authors.lastname: Cui
authors.forename: William C
authors.initials: WC
authors.lastname: Chen
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Patrick
authors.initials: P
authors.lastname: Killela
authors.forename: Chunhui
authors.initials: C
authors.lastname: Di
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Payne
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Roger
authors.initials: R
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002330:Carmustine
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