title: A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas.
abstract: Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor-initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies.
authors.affiliation: The Arthur and Sonia Labatt's Brain Tumor Research Centre, The Hospital for Sick Children's Research Institute, Toronto Western Hospital, University of Toronto, Toronto M5A 2N4, Ontario, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.forename: Amparo
authors.initials: A
authors.lastname: Wolf
authors.forename: Diana M
authors.initials: DM
authors.lastname: Munoz
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Aaron
authors.initials: A
authors.lastname: Gajadhar
authors.forename: Andres
authors.initials: A
authors.lastname: Restrepo
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000502:physiology; D045643:DNA Repair Enzymes / Q000502:physiology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide