Mechanism of NURP1 in temozolomide resistance in hypoxiatreated glioma cells via the KDM3A/TFEB axis  

作　　者：TAO LI XIN FU JIE WANG WEI SHANG XIAOTONG WANG LINYUN ZHANG JUN LI 

机构地区：[1]Department of Neurosurgery,First Affiliated Hospital of Dalian Medical University,Dalian,116011,China

出　　处：《Oncology Research》2023年第3期345-359,共15页肿瘤学研究（英文）

基　　金：supported by Scientific Research Project of Education Department of Liaoning Province(Grant Number LJKZ0854).

摘　　要：Temozolomide(TMZ)resistance is a major obstacle in glioma treatment.Nuclear protein-1(NUPR1)is a regulator of glioma progression.This study investigated the mechanism of NUPR1 in TMZ resistance in hypoxiatreated glioma cells and its mechanism in modulating autophagy.We treated TMZ-resistant cells U251-TMZ and T98G-TMZ to normoxia or hypoxia and silenced NUPR1 in hypoxia-treated U251-TMZ and T98G-TMZ cells to assess cell viability,proliferation,apoptosis,LC3-II/LC3-I and p62 expressions,and autophagic flux under different concentrations of TMZ.We found that hypoxia upregulated NUPR1 expression and autophagy while NUPR1 silencing suppressed hypoxia-induced TMZ resistance and autophagy in glioma cells.We also investigated the interaction between NUPR1 and lysine demethylase 3A(KDM3A),as well as the enrichments of KDM3A and H3 lysine 9 dimethylation(H3K9me2)in the transcription factor EB(TFEB)promoter region.Our results suggest that hypoxia-induced NUPR1 promotes TFEB transcription by binding to KDM3A and reducing H3K9me2 levels,thereby augmenting glioma cell autophagy and TMZ resistance.Moreover,the overexpression of KDM3A or TFEB promoted glioma cell autophagy.In a xenograft tumor model,silencing NUPR1 suppressed TMZ resistance in glioma cells in vivo.Overall,our findings highlight a mechanism by which NUPR1 enhances glioma cell autophagy and TMZ resistance via the KDM3A/TFEB axis.

关 键 词：NUPR1 AUTOPHAGY TMZ resistance GLIOMA KDM3A 

分 类 号：R739.41[医药卫生—肿瘤]