Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma
Open Access
- 29 January 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 3 (1), 1160
- https://doi.org/10.1038/srep01160
Abstract
Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ-induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM.This publication has 62 references indexed in Scilit:
- Qualitative Network Modeling of the Myc-p53 Control System of Cell Proliferation and DifferentiationBiophysical Journal, 2011
- p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53Cell Death & Differentiation, 2011
- Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancerProceedings of the National Academy of Sciences of the United States of America, 2011
- Activation of AMP-activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via p53 Activation and mTORC1 InhibitionPublished by Elsevier BV ,2010
- TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAsNature, 2010
- TATA-binding Protein (TBP)-like Protein Is Engaged in Etoposide-induced Apoptosis through Transcriptional Activation of Human TAp63 GenePublished by Elsevier BV ,2009
- TAp63 induces senescence and suppresses tumorigenesis in vivoNature, 2009
- p53 represses c-Myc through induction of the tumor suppressor miR-145Proceedings of the National Academy of Sciences of the United States of America, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Radiotherapy plus Concomitant and Adjuvant Temozolomide for GlioblastomaNew England Journal of Medicine, 2005