Scholarlink

<p>Glioblastoma (GBM) remains a lethal brain tumor due to therapy resistance. While autophagy contributes to temozolomide (TMZ) resistance, its regulation is incompletely understood. This study investigates the role of replication factor <i>RFC4</i>, which is associated with poor prognosis and TMZ resistance in GBM. Multi-omics analyses and molecular experiments reveal that TMZ-induced chromatin accessibility enables transcription factor YY1 to bind the <i>RFC4</i> promoter and upregulate its expression. RFC4, in turn, stabilizes the kinase STK38, which is essential for autophagosome formation. The RFC4-STK38 interaction facilitates BECN1 recruitment, thereby activating autophagy. Phosphorylation of STK38 at T444 stabilizes this complex, whereas a phospho-deficient mutant impairs autophagy. In vivo, RFC4 overexpression confers TMZ resistance, reversible by autophagy inhibition. Thus, our findings identify the RFC4-STK38-BECN1 axis as a mechanism underlying TMZ resistance and a potential target for precision therapy in GBM.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月23日

查看全文
  • Min Mao,
  • Hang Ji,
  • Wen-Qian Yu,
  • Qu-Jing Gai,
  • Qiang Sun,
  • Qian Yan,
  • Sen-Lin Xu,
  • Meng-Li Zhu,
  • Mei-Hua Qu,
  • Han-Min Liu,
  • Jean-Philipe Hugnot,
  • Xi He,
  • Xin Wang,
  • Yan Wang

摘要

Glioblastoma (GBM) remains a lethal brain tumor due to therapy resistance. While autophagy contributes to temozolomide (TMZ) resistance, its regulation is incompletely understood. This study investigates the role of replication factor RFC4, which is associated with poor prognosis and TMZ resistance in GBM. Multi-omics analyses and molecular experiments reveal that TMZ-induced chromatin accessibility enables transcription factor YY1 to bind the RFC4 promoter and upregulate its expression. RFC4, in turn, stabilizes the kinase STK38, which is essential for autophagosome formation. The RFC4-STK38 interaction facilitates BECN1 recruitment, thereby activating autophagy. Phosphorylation of STK38 at T444 stabilizes this complex, whereas a phospho-deficient mutant impairs autophagy. In vivo, RFC4 overexpression confers TMZ resistance, reversible by autophagy inhibition. Thus, our findings identify the RFC4-STK38-BECN1 axis as a mechanism underlying TMZ resistance and a potential target for precision therapy in GBM.