STUB1-SMYD2 Axis Regulated Drug Resistance in Glioma cells

Abstract Aim: SMYD2 is an important epigenetic regulator that methylates histone and non-histone proteins. This study aims to investigate SMYD2 as an oncogene of gliomas and explore its degradation mechanism induced by cisplatin.Methods: Tumor tissue microarray of 441 glioma patients was collected for SMYD2 immunohistochemistry staining. Kaplan-Meier survival curves were constructed by using he overall survival. mRNA-sequencing analysis was detected for understanding the downstream mechanisms mediated by SMYD2. The half-inhibitory concentrations (IC50) of temozolomide and cisplatin in AZ505-treated and control cells were calculated. Thepotential E3 ubiquitin ligase of SMYD2 was predicted in UbiBrowser and confirmed by knockdown test. The effect of SMYD2 and its E3 ligase on gliomas apoptosis and migration were determined via cell-function assays.Results: High SMYD2 expression correlated with a high WHO stage (P=0.004) and a low survival probability (P=0.012). The inhibition of SMYD2 suppressed the process of EMT by downregulating the expression of COL1A1. AZ505 treatment significantly increased drug sensitivity of glioma cells. And the expression of SMYD2 was markedly reduced by cisplatin treatment via STUB1 mediated degradation. The knockdown of STUB1 could partly reverse the cell function impairment induced by cisplatin.Conclusion: These findings suggested that SMYD2 could be a potential drug target for the treatment of gliomas, and STUB1-mediated degradation of SMYD2 plays an important role in reversing chemotherapy resistance in gliomas.