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Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2‐Mediated MLH1 Intron Retention
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Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2‐Mediated MLH1 Intron Retention
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Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2‐Mediated MLH1 Intron Retention
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Journal Article
Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2‐Mediated MLH1 Intron Retention
2024
Overview
Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). Lactylation is a novel post‐translational modification that is involved in various tumors. However, whether lactylation plays a role in GBM TMZ resistance remains unclear. Here it is found that histone H3K9 lactylation (H3K9la) confers TMZ resistance in GBM via LUC7L2‐mediated intron 7 retention of MLH1. Mechanistically, lactylation is upregulated in recurrent GBM tissues and TMZ‐resistant cells, and is mainly concentrated in histone H3K9. Combined multi‐omics analysis, including CUT&Tag, SLAM‐seq, and RNA‐seq, reveals that H3K9 lactylation is significantly enriched in the LUC7L2 promoter and activates LUC7L2 transcription to promote its expression. LUC7L2 mediates intron 7 retention of MLH1 to reduce MLH1 expression, and thereby inhibit mismatch repair (MMR), ultimately leading to GBM TMZ resistance. Of note, it is identified that a clinical anti‐epileptic drug, stiripentol, which can cross the blood–brain barrier and inhibit lactate dehydrogenase A/B (LDHA/B) activity, acts as a lactylation inhibitor and renders GBM cells more sensitive to TMZ in vitro and in vivo. These findings not only shed light on the mechanism of lactylation in GBM TMZ resistance but also provide a potential combined therapeutic strategy for clinical GBM treatment. Lactylation is upregulated in recurrent glioblastoma (GBM) tissues and temozolomide (TMZ)‐resistant cells, mainly concentrated in histone H3K9. H3K9 lactylation activates LUC7L2 transcription. LUC7L2 mediates MLH1 intron 7 retention to reduce MLH1 expression, thereby inhibit mismatch repair (MMR), ultimately leading to TMZ resistance. Targeting lactylation with stiripentol to enhance TMZ sensitivity is a promising combined therapeutic strategy for clinical GBM treatment.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
Subject
/ Antineoplastic Agents, Alkylating - pharmacology
/ Antineoplastic Agents, Alkylating - therapeutic use
/ Brain Neoplasms - drug therapy
/ Brain Neoplasms - metabolism
/ Drug Resistance, Neoplasm - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Glioma
/ Humans
/ LUC7L2
/ Mice
/ MutL Protein Homolog 1 - genetics
/ MutL Protein Homolog 1 - metabolism
/ Proteins
/ Tumors
