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Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

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.

SUBMITTER: Yamaki T

PROVIDER: S-EPMC3557454 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

Yamaki Tomohiro T Suenaga Yusuke Y Iuchi Toshihiko T Alagu Jennifer J Takatori Atsushi A Itami Makiko M Araki Akinobu A Ohira Miki M Inoue Masahiro M Kageyama Hajime H Yokoi Sana S Saeki Naokatsu N Nakagawara Akira A

Scientific reports 20130129

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 i ...[more]

PMID: 23362460

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Project description:ObjectiveTemozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular mechanisms in temozolomide therapy for glioblastoma involving LINC00470.MethodsBioinformatics analysis was conducted to predict the potential mechanism of LINC00470 in glioblastoma, which was validated by dual-luciferase reporter, RIP, ChIP, and RNA pull-down assays. LINC00470 expression and the predicted downstream transcription factor early growth response 2 (EGR2) were detected in the collected brain tissues from glioblastoma patients. Following temozolomide treatment and/or gain- and loss-of-function approaches in glioblastoma cells, cell viability, invasion, migration, cycle distribution, angiogenesis, autophagy, and apoptosis were measured. In addition, the expression of mesenchymal surface marker proteins was assessed by western blot. Tumor xenograft in nude mice was conducted for in vivo validation.ResultsMechanistic analysis and bioinformatics analysis revealed that LINC00470 transcriptionally activated SRY-related high-mobility-group box 4 (SOX4) through the transcription factor EGR2. LINC00470 and EGR2 were highly expressed in brain tissues of glioblastoma patients. LINC00470 and EGR2 mRNA expression gradually decreased with increasing concentrations of temozolomide in glioblastoma cells, and SOX4 expression was reduced in cells by temozolomide and LINC00470 knockdown. Temozolomide treatment induced cell cycle arrest, diminished cell viability, migration, invasion, and angiogenesis, and increased apoptosis and autophagy in glioblastoma, which was counteracted by overexpressing LINC00470 or SOX4 but was further promoted by LINC00470 knockdown. Temozolomide restrained glioblastoma growth and angiogenesis in vivo, while LINC00470 or SOX4 overexpression nullified but LINC00470 knockdown further facilitated these trends.ConclusionConclusively, temozolomide repressed glioblastoma progression by repressing the LINC00470/EGR2/SOX4 axis.

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Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

Publications

Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

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