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Identification of TMZ resistance‐associated histone post‐translational modifications in glioblastoma using multi‐omics data
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Identification of TMZ resistance‐associated histone post‐translational modifications in glioblastoma using multi‐omics data
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Journal Article
Identification of TMZ resistance‐associated histone post‐translational modifications in glioblastoma using multi‐omics data
2024
Overview
Backgroud Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ. Methods To explore the mechanisms underlying resistance, we developed two TMZ‐resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ‐resistant cell lines revealed that alterations in histone post‐translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi‐omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance. Results We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single‐cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy. Conclusions The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM. The acetylation of histone H3 at lysine 9 leads to an open chromatin structure at the MGMT gene locus, facilitating the binding of transcription factors SP1 to the promoter and enhancer regions, resulting in increased transcription of MGMT, thereby contributing to the TMZ resistance in GBM cells.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
