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.