MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Autor:	Hansen LJ; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina., Sun R; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.; Scientific Research Center, China-Japan Union Hospital, Jilin University, Jilin, China., Yang R; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Singh SX; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Chen LH; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Pirozzi CJ; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Moure CJ; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Hemphill C; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Carpenter AB; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Healy P; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina., Ruger RC; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Chen CJ; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina., Greer PK; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Zhao F; Genetron Health Technologies, Inc., Research Triangle Park, North Carolina., Spasojevic I; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Grenier C; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina., Huang Z; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina., Murphy SK; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina., McLendon RE; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., Friedman HS; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Friedman AH; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Herndon JE 2nd; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina., Sampson JH; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Keir ST; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Bigner DD; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina., Yan H; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.; Department of Pathology, Duke University Medical Center, Durham, North Carolina., He Y; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina. yiping.he@dm.duke.edu.; Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Jul 01; Vol. 79 (13), pp. 3383-3394. Date of Electronic Publication: 2019 Apr 30.
DOI:	10.1158/0008-5472.CAN-18-1010
Abstrakt:	Homozygous deletion of methylthioadenosine phosphorylase ( MTAP ) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1 /CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1 /CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP -null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133 + cells in MTAP -null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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