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

Cancer research (2019-05-02)
Landon J Hansen, Ran Sun, Rui Yang, Simranjit X Singh, Lee H Chen, Christopher J Pirozzi, Casey J Moure, Carlee Hemphill, Austin B Carpenter, Patrick Healy, Ryan C Ruger, Chin-Pu J Chen, Paula K Greer, Fangping Zhao, Ivan Spasojevic, Carole Grenier, Zhiqing Huang, Susan K Murphy, Roger E McLendon, Henry S Friedman, Allan H Friedman, James E Herndon, John H Sampson, Stephen T Keir, Darell D Bigner, Hai Yan, Yiping He
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Minimum Essential Medium Eagle, With Earle′s salts, L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Roche
DIG-High Prime DNA Labeling and Detection Starter Kit II, sufficient for 12 labeling reactions (10 ng to 3 μg per assay), sufficient for 24 blots (blots of 100 cm2)