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Differentiated embryonic chondrocyte-expressed gene 1 promotes temozolomide resistance by modulating the SP1-MGMT axis in glioblastoma.

ABSTRACT: Glioblastoma multiforme (GBM) is a malignant brain tumor with a high mortality rate and poor prognosis. Temozolomide (TMZ) is a first-line drug against GBM, but resistance limits its use. We previously reported that differentiated embryonic chondrocyte (DEC1) expression is associated with TMZ resistance and poor prognosis in GBM; however, the underlying mechanism remains unclear. By using glioma cell lines with stably overexpressed or silenced DEC1, we examined the effects of DEC1 on TMZ sensitivity using proliferation assays, Western blotting, and flow cytometry. We demonstrated that DEC1 overexpression suppressed, whereas DEC1 knockdown enhanced, TMZ-induced cell apoptosis in methylguanine methyltransferase (MGMT)-positive T98G and LN18 cells but not in MGMT-negative U251 cells. Mechanistically, DEC1 positively regulated MGMT through specificity protein 1 (SP1). MGMT silencing in DEC1-overexpressing cells or overexpression in DEC1-silenced cells abrogated DEC1's effects on TMZ sensitivity, and siRNA-mediated SP1 knockdown phenocopied TMZ sensitivity, which was rescued by MGMT overexpression. Thus, DEC1 may control TMZ resistance via the SP1-MGMT axis. Immunohistochemical staining of the human glioma tissue microarray revealed that the expression levels of DEC1 and MGMT were correlated. Therefore, DEC1 expression has a predictive value for TMZ resistance and poor outcome in glioma patients, and is a novel therapeutic target in TMZ-resistant glioma.

SUBMITTER: Lv W

PROVIDER: S-EPMC8129344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: Not available

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A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

2018-07-13 | GSE113816 | GEO

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