MicroRNA strand ratio disarray promotes temozolomide resistance in glioblastoma

Disarray in microRNA (miRNA) strand selection is associated with multiple tumors. However, the mechanisms underlying miRNA strand selection-driven temozolomide (TMZ) resistance in glioblastoma (GBM) remain unexplored.

Here, we observed that the strand selection disarray of miR-92b contributes to enhancing TMZ resistance. The pattern of higher expression of miR-92b-3p and lower expression of miR-92b-5p is significantly correlated with TMZ resistance. In TMZ-resistant GBM cells, miR-92b-3p and miR-92b-5p increased the enrichment of H3K27ac in the COL7A1 promoter region by divergently targeting HDAC9 and FOXP3, thereby elevating COL7A1 expression and mediating collagen deposition. In addition, TUT4 regulated strand selection of pre-miR-92b through uridylation, promoting preference for the 3' strand (3p). The TUT4 inhibitor aurothioglucose hydrate (ATG-H) blocked the miR-92b strand selection disarray and restored TMZ sensitivity in TMZ-resistant GBM cells.

Our study demonstrates that TUT4-mediated elevation of the miR-92b-3p/-5p ratio promotes COL7A1 transcription via silencing HDAC9 and alleviation of FOXP3 targeting, leading to collagen deposition and heightened TMZ resistance. Our results suggest that targeting miR-92b strand selection may serve as a potential therapeutic strategy for sensitizing GBM to TMZ.