Title:EZH2-regulated PARP-1 Expression is a Likely Mechanism for the
Chemoresistance of Gliomas to Temozolomide
Volume: 24
Issue: 3
关键词:
EZH2,胶质瘤,化疗耐药,替莫唑胺,DNA修复,PARP1。
摘要:
Background: 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.
Objective: To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms.
Methods: 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.
Results: 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.
Conclusion: 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.