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0This research identifies the transcription factor E2F6 as a primary driver of temozolomide (TMZ) resistance and poor clinical outcomes in glioblastoma patients. The study reveals that E2F6 actively suppresses the expression of SH3GL2, a protein that otherwise facilitates the export of HMGB1 out of tumor cells. When E2F6 levels are high, HMGB1 is retained within the cell to assist in DNA repair, effectively shielding the cancer from chemotherapy. By experimental depletion of E2F6, researchers restored SH3GL2 levels, which triggered the secretion of HMGB1 into the extracellular space. This process not only leaves the tumor vulnerable by impairing its DNA repair mechanisms but also alerts the immune system by promoting M1 macrophage polarization. Ultimately, the findings suggest that targeting this E2F6/SH3GL2/HMGB1 signaling axis could enhance the effectiveness of standard treatments and stimulate an anti-tumor immune response.
References:
Gong C, Chen M, Zeng Y, et al. E2F6 mediates temozolomide resistance and immunosuppression in glioblastoma by repressing SH3GL2-dependent HMGB1 secretion[J]. Cell Death & Disease, 2026.
