APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death
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Yu Wang1,4,*, Shaofang Wu1,*, Siyuan Zheng2, Shuzhen Wang1, Arjun Wali1, Ravesanker Ezhilarasan3, Erik P. Sulman3, Dimpy Koul1 and W.K. Alfred Yung1
1Brain Tumor Center, Departments of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
*These authors contributed equally to this work
W.K. Alfred Yung, email: [email protected]
Dimpy Koul, email: [email protected]
Keywords: mesenchymal gliomas, APOBEC3G, TGFβ signaling, radiation and cell death
Received: November 02, 2016 Accepted: April 11, 2017 Published: April 21, 2017
Genomic, transcriptional, and proteomic analyses of brain tumors reveal that subtypes differ in their pathway activity, progression, and response to therapy. We performed an expression profiling of Glioma Initiating Cells (GICs) and comparative analysis between different groups of GICs indicates major variations in gene expression. Hierarchical clustering analysis revealed groups of GICs reflecting their heterogeneity, and among some of the genes as major regulators of mesenchymal phenotype, we identified ABOBEC3G as one of the most discriminating genes in mesenchymal group. ABOBEC3G revealed a strong correlation with overall survival in TCGA GBM patient cohorts. APOBEC3G regulates cell invasion and silencing of this gene in GICs inhibits cell invasion and also glioma sphere initiation. APOBEC3G controls invasion through TGFβ/Smad2 pathway by regulating Smad2 target genes Thrombospondin 1, matrix metallopeptidase 2 and TIMP metallopeptidase inhibitor 1. We also show that targeting APOBEC3G can sensitize cancer cells to radiation induced cell death by attenuating activation of the DNA repair pathway. This response is mainly shown by decreased pChk2 expression in knockdown APOBEC3G cells. Taken together, we show that APOBEC3G gene is a mesenchymal enriched gene that controls invasion and knockdown of APOBEC3G sensitizes cells to radiation induced cell death, suggesting that APOBEC3G can be considered for use in stratifying patients with GBM for prognostic considerations.
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