EZH2-regulated PARP-1 Expression is a Likely Mechanism for the Chemoresistance of Gliomas to Temozolomide.

Chemoresistance in gliomas accounts for the major cause of tumor progress and recurrence during comprehensive treatment with alkylating agents including temozolomide (TMZ). The oncogenic role of Enhancer of zeste homolog 2 (EZH2) has been identified in many solid malignancies including gliomas, though the accurate effect of EZH2 on chemotherapy resistance of gliomas has been elusive. To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms. Immunohistochemistry (IHC) and Reverse transcription-quantitative (RT-q) PCR, and western blot assay were performed for expressional analysis. Cell Counting Kit-8 (CCK-8) assay was applied to determine the TMZ sensitivity. EZH2-silencing lentivirus was generated for mechanic study. EZH2 was overexpressed in gliomas both at the transcriptional and protein levels. EZH2 level in glioma cell lines was positively correlated with resistance to TMZ, represented by the 50% inhibition rate (IC50). Moreover, there was increased TMZ sensitivity in EZH2-inhibited glioma cells than in the control cells. Furthermore, we determined that PARP1 was a common molecule among the downregulated DNA repair proteins in both U251 and U87 glioma cell lines after EZH2 inhibition. Specifically, we observed a spontaneous increase of PARP1 expression with TMZ treatment and interestingly, the increase of PARP1 could be also reduced by EZH2 inhibition in the glioma cells. Finally, combined treatment with lentivirus-induced EZH2 inhibition and a PARP1 inhibitor dramatically enhanced TMZ cytotoxicity compared with either one alone. EZH2-PARP-1 signaling axis is possibly responsible for the chemoresistance of gliomas to TMZ. Simultaneously inhibiting these two genes may improve the outcome of TMZ chemotherapy.

Liang Q ，Wang B ，Zhang C ，Song C ，Wang J ，Sun W ，Jiang L ，Lin J ... -  《-》

ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma.

Rationale: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed. Methods: We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma. Results: We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models. Conclusions: The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.

Han B ，Meng X ，Wu P ，Li Z ，Li S ，Zhang Y ，Zha C ，Ye Q ，Jiang C ，Cai J ，Jiang T ... -  《Theranostics》

lncRNA TUG1 inhibits the cancer stem cell‑like properties of temozolomide‑resistant glioma cells by interacting with EZH2.

Cao Y ，Chai W ，Wang Y ，Tang D ，Shao D ，Song H ，Long J ... -  《-》

Gene expression profiling predicts response to temozolomide in malignant gliomas.

Yoshino A ，Ogino A ，Yachi K ，Ohta T ，Fukushima T ，Watanabe T ，Katayama Y ，Okamoto Y ，Naruse N ，Sano E ，Tsumoto K ... -  《-》

The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents.

Chen CC ，Taniguchi T ，D'Andrea A 《JOURNAL OF MOLECULAR MEDICINE-JMM》