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<p>Temozolomide (TMZ) resistance remains a major obstacle in glioblastoma (GBM) therapy. Here, we identified E2F6 as a critical driver of TMZ resistance in GBM. E2F6 expression was significantly elevated in glioma tissues and correlated with advanced tumor grade, recurrence, and poor prognosis. Functionally, E2F6 depletion sensitized GBM cells to TMZ, suppressing proliferation and promoting apoptosis both in vitro and in vivo. Mechanistically, E2F6 directly bound to the SH3GL2 promoter and transcriptionally repressed its expression. SH3GL2 acted as a key downstream effector of E2F6, as SH3GL2 silencing abolished the chemosensitizing effects induced by E2F6 knockdown. Further investigation revealed that SH3GL2 promoted HMGB1 secretion through BAR domain-mediated interaction with CHMP4B and SH3 domain-dependent binding to HMGB1. Enhanced HMGB1 secretion reduced intracellular HMGB1 retention, impaired DNA damage repair, and increased TMZ-induced DNA damage. In addition, extracellular HMGB1 promoted M1 macrophage polarization, thereby enhancing anti-tumor immune responses. Collectively, our findings identify the E2F6/SH3GL2/HMGB1 axis as a previously unrecognized mechanism linking DNA repair and tumor immune regulation during TMZ resistance, and suggest that targeting this pathway may represent a promising therapeutic strategy for GBM.</p><p></p>

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E2F6 mediates temozolomide resistance and immunosuppression in glioblastoma by repressing SH3GL2-dependent HMGB1 secretion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Chuandong Gong,
  • Ming Chen,
  • Yuxin Zeng,
  • Zhihong Zhou,
  • Jianghua Zhu,
  • Yi Xu,
  • Xingen Zhu,
  • Kai Huang

摘要

Temozolomide (TMZ) resistance remains a major obstacle in glioblastoma (GBM) therapy. Here, we identified E2F6 as a critical driver of TMZ resistance in GBM. E2F6 expression was significantly elevated in glioma tissues and correlated with advanced tumor grade, recurrence, and poor prognosis. Functionally, E2F6 depletion sensitized GBM cells to TMZ, suppressing proliferation and promoting apoptosis both in vitro and in vivo. Mechanistically, E2F6 directly bound to the SH3GL2 promoter and transcriptionally repressed its expression. SH3GL2 acted as a key downstream effector of E2F6, as SH3GL2 silencing abolished the chemosensitizing effects induced by E2F6 knockdown. Further investigation revealed that SH3GL2 promoted HMGB1 secretion through BAR domain-mediated interaction with CHMP4B and SH3 domain-dependent binding to HMGB1. Enhanced HMGB1 secretion reduced intracellular HMGB1 retention, impaired DNA damage repair, and increased TMZ-induced DNA damage. In addition, extracellular HMGB1 promoted M1 macrophage polarization, thereby enhancing anti-tumor immune responses. Collectively, our findings identify the E2F6/SH3GL2/HMGB1 axis as a previously unrecognized mechanism linking DNA repair and tumor immune regulation during TMZ resistance, and suggest that targeting this pathway may represent a promising therapeutic strategy for GBM.