title: A novel PTEN/mutant p53/c-Myc/Bcl-XL axis mediates context-dependent oncogenic effects of PTEN with implications for cancer prognosis and therapy.
abstract: Phosphatase and tensin homolog located on chromosome 10 (PTEN) is one of the most frequently mutated tumor suppressors in human cancer including in glioblastoma. Here, we show that PTEN exerts unconventional oncogenic effects in glioblastoma through a novel PTEN/mutant p53/c-Myc/Bcl-XL molecular and functional axis. Using a wide array of molecular, genetic, and functional approaches, we demonstrate that PTEN enhances a transcriptional complex containing gain-of-function mutant p53, CBP, and NFY in human glioblastoma cells and tumor tissues. The mutant p53/CBP/NFY complex transcriptionally activates the oncogenes c-Myc and Bcl-XL, leading to increased cell proliferation, survival, invasion, and clonogenicity. Disruption of the mutant p53/c-Myc/Bcl-XL axis or mutant p53/CBP/NFY complex reverses the transcriptional and oncogenic effects of PTEN and unmasks its tumor-suppressive function. Consistent with these data, we find that PTEN expression is associated with worse patient survival than PTEN loss in tumors harboring mutant p53 and that a small molecule modulator of p53 exerts greater antitumor effects in PTEN-expressing cancer cells. Altogether, our study describes a new signaling pathway that mediates context-dependent oncogenic/tumor-suppressive role of PTEN. The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53.
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Tang
authors.forename: Napoleon
authors.initials: N
authors.lastname: Butler
authors.forename: Jungeun
authors.initials: J
authors.lastname: Kim
authors.forename: Fadila
authors.initials: F
authors.lastname: Guessous
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: James
authors.initials: J
authors.lastname: Mandell
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D017209:Apoptosis / Q000235:genetics; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D023081:CCAAT-Binding Factor; C489427:MYC protein, human; C492061:NFYA protein, human; D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc; D012795:Sialoglycoproteins; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C571744:bone sialoprotein (35-62), human; D051059:PTEN Phosphohydrolase
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