Open AccessHOTAIR/miR‐125 axis‐mediated Hexokinase 2 expression promotes chemoresistance in human glioblastoma
Author(s) -
Zhang Jinnan,
Chen Guangyong,
Gao Yufei,
Liang Huaxin
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15233
Subject(s) - hotair , cancer research , temozolomide , cell growth , glioma , apoptosis , biology , u87 , downregulation and upregulation , microrna , long non coding rna , biochemistry , genetics , gene
Drug resistance is one of the major obstacles in glioblastoma (GBM) treatments using temozolomide (TMZ) based conventional chemotherapy. Recent studies revealed that Hexokinase 2 (HK2)‐mediated glycolysis is one of the sources, as the association of chemoresistance and the expression of HK2 was confirmed in multiple cancers. However, there has been little knowledge of the functional contribution of HK2 to TMZ resistance in GBM. In our study, we found that HK2 expression is crucial for GBM proliferation and chemoresistance. In contrast to the healthy brain, HK2 expression is much higher in human GBM, especially in those patients with GBM recurrence. High HK2 expression is negatively related to the overall survival in GBM patients. HK2 depletion in GBM cells suppressed the GBM cell proliferation and increased sensitivity to TMZ‐induced apoptosis. Both HK2‐mediated glycolysis and mitochondria permeability transition pore opening (MPTP) were associated with its function in chemoresistance. Furthermore, we also revealed that the abnormal expression of HK2 was modulated by the expression of HOTAIR, a long non‐coding RNA (lncRNA). The absence of HOTAIR in GBM cells suppressed the HK2 expression in protein and mRNA level and, therefore, inhibited the cell proliferation and enhanced the cytotoxicity of TMZ both in vivo and in vitro. HOTAIR promoted the expression of HK2 by targeting mir‐125, which suppressed the GBM cell proliferation and increased the TMZ‐induced apoptosis. These findings shed light on a new therapeutic strategy in modulating HOTAIR/miR‐125, which may interfere with the expression of HK2, and enhance the therapeutic sensitivity of GBM to TMZ.