Open Access

ARTICLE

Mechanism of NURP1 in temozolomide resistance in hypoxia-treated glioma cells via the KDM3A/TFEB axis

by TAO LI^#, XIN FU^#, JIE WANG, WEI SHANG, XIAOTONG WANG, LINYUN ZHANG, JUN LI^*

Department of Neurosurgery, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

* Corresponding Author: JUN LI. Email:

Oncology Research 2023, 31(3), 345-359. https://doi.org/10.32604/or.2023.028724

Received 04 January 2023; Accepted 14 March 2023; Issue published 22 May 2023

Abstract

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 hypoxia-treated 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.

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