Scholarlink

<p>Adaptive resistance to MAPK inhibitors remains a major clinical obstacle in BRAF-mutant melanoma, driven by reversible transcriptional and epigenetic reprogramming. Previous studies have implicated loss of SRY-box transcription factor 10 (SOX10) and concurrent activation of TGF-β signaling in this process, but the molecular link between them has remained unresolved. Here, we identify a SOX10-miR-106a/363-TGFBR2 regulatory axis that governs adaptive resistance. SOX10 directly activates transcription of the miR-106a/363 cluster through a distal cis-regulatory element. In turn, the miR-106a/363 cluster members miR-106a-5p and miR-20b-5p suppress TGFBR2 post-transcriptionally, while miR-363-3p indirectly reduces TGFBR2 expression by targeting SOX4, a transcriptional activator of TGFBR2. This dual-layered repression restrains TGF-β signaling and maintains drug sensitivity. Loss of SOX10 diminishes miR-106a/363 expression, derepresses TGFBR2, and promotes a mesenchymal-like, drug-tolerant state. Restoring miR-106a/363 expression partially re-sensitizes melanomas to RAF inhibitors in vivo. These findings reveal a previously unrecognized regulatory circuit linking SOX10 to TGF-β signaling and highlight the miR-106a/363 cluster as a potential therapeutic target to overcome adaptive resistance in melanoma.</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

SOX10-mediated regulation of the MiR-106a/363 cluster drives RAF inhibitor resistance in BRAF-mutant melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月18日

查看全文
  • Ying Li,
  • Yu-le Yong,
  • Zhe Zhi,
  • ZhenZhen Lu,
  • Zongguan Huang,
  • Lanlan Cui,
  • Mo Zhang,
  • Zihao Wu,
  • Yiming Hu,
  • Guanfei Zhang,
  • Xiaofei Zhao,
  • Shujun Han,
  • Yan Zheng,
  • Yongping Shao

摘要

Adaptive resistance to MAPK inhibitors remains a major clinical obstacle in BRAF-mutant melanoma, driven by reversible transcriptional and epigenetic reprogramming. Previous studies have implicated loss of SRY-box transcription factor 10 (SOX10) and concurrent activation of TGF-β signaling in this process, but the molecular link between them has remained unresolved. Here, we identify a SOX10-miR-106a/363-TGFBR2 regulatory axis that governs adaptive resistance. SOX10 directly activates transcription of the miR-106a/363 cluster through a distal cis-regulatory element. In turn, the miR-106a/363 cluster members miR-106a-5p and miR-20b-5p suppress TGFBR2 post-transcriptionally, while miR-363-3p indirectly reduces TGFBR2 expression by targeting SOX4, a transcriptional activator of TGFBR2. This dual-layered repression restrains TGF-β signaling and maintains drug sensitivity. Loss of SOX10 diminishes miR-106a/363 expression, derepresses TGFBR2, and promotes a mesenchymal-like, drug-tolerant state. Restoring miR-106a/363 expression partially re-sensitizes melanomas to RAF inhibitors in vivo. These findings reveal a previously unrecognized regulatory circuit linking SOX10 to TGF-β signaling and highlight the miR-106a/363 cluster as a potential therapeutic target to overcome adaptive resistance in melanoma.