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<p>Colorectal cancer progression involves dysregulated signaling pathways such as Hippo-YAP, but upstream regulators remain poorly defined. Here we demonstrate that oxysterol-binding protein-like 3 (OSBPL3) modulates Hippo-YAP signaling to drive tumor aggressiveness. Analysis of clinical specimens and experimental models shows that elevated OSBPL3 levels in colorectal cancer tissues correlate with shortened patient survival. Depleting OSBPL3 impairs cancer cell proliferation and invasion and induces cell cycle arrest, while its overexpression accelerates tumor growth. Mechanistic studies reveal that OSBPL3 binds 14-3-3 proteins to promote YAP1 nuclear translocation, activating downstream oncogenic pathways. Notably, tumors with high OSBPL3 expression exhibit resistance to MEK inhibitors, but this resistance is overcome by YAP1 suppression or combined YAP/MEK inhibition in patient-derived organoids. These results establish OSBPL3 as a critical Hippo-YAP pathway regulator and propose targeting OSBPL3-mediated signaling as a therapeutic strategy for colorectal cancers with Hippo pathway alterations.</p>

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OSBPL3 drives colorectal cancer progression via Hippo-YAP signaling and modulates MEK inhibitor sensitivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Yuchen Zhong,
  • Chaojing Zheng,
  • Zitong Wang,
  • Weiyuan Zhang,
  • Hongyu Wu,
  • Jun Luo,
  • Hao Zhang,
  • Chunlin Wang,
  • Chenkai Zhang,
  • Hanqing Hu,
  • Ziming Yuan,
  • Meng Wang,
  • Qian Zhang,
  • Guiyu Wang

摘要

Colorectal cancer progression involves dysregulated signaling pathways such as Hippo-YAP, but upstream regulators remain poorly defined. Here we demonstrate that oxysterol-binding protein-like 3 (OSBPL3) modulates Hippo-YAP signaling to drive tumor aggressiveness. Analysis of clinical specimens and experimental models shows that elevated OSBPL3 levels in colorectal cancer tissues correlate with shortened patient survival. Depleting OSBPL3 impairs cancer cell proliferation and invasion and induces cell cycle arrest, while its overexpression accelerates tumor growth. Mechanistic studies reveal that OSBPL3 binds 14-3-3 proteins to promote YAP1 nuclear translocation, activating downstream oncogenic pathways. Notably, tumors with high OSBPL3 expression exhibit resistance to MEK inhibitors, but this resistance is overcome by YAP1 suppression or combined YAP/MEK inhibition in patient-derived organoids. These results establish OSBPL3 as a critical Hippo-YAP pathway regulator and propose targeting OSBPL3-mediated signaling as a therapeutic strategy for colorectal cancers with Hippo pathway alterations.