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Inhibition of Histone Deacetylation Potentiates the Evolution of Acquired Temozolomide Resistance Linked to MGMT Upregulation in Glioblastoma Xenografts
Blocking histone deacetylation may increase the development of drug resistance linked to MGMT in glioblastoma models
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Abstract
Upregulation of O6-methylguanine-DNA methyltransferase (MGMT) expression was observed in 3 of the 5 resistant glioblastoma multiforme xenografts.
- Temozolomide resistance in glioblastoma multiforme may be linked to increased MGMT expression.
- No significant changes in MGMT promoter methylation were found between parental and resistant tumor samples.
- An association was detected between MGMT upregulation and higher levels of acetylation of a specific histone mark (H3K9-ac) along with lower levels of another mark (H3K9-me2) in certain resistant tumors.
- In one resistant line, increased MGMT expression correlated with greater recruitment of specific transcription factors to the MGMT promoter.
- Combined treatment with temozolomide and an HDAC inhibitor may enhance MGMT overexpression, contributing to the development of resistance.
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