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<p>Colorectal cancer (CRC) ranks as the third most common malignancy worldwide, with metastasis representing the primary cause of mortality. Aberrant activation of the Wnt/β-catenin pathway drives epithelial‒mesenchymal transition (EMT) and CRC metastasis, making β-catenin a key therapeutic target. Josephin domain containing 2 (JOSD2), a deubiquitinase with protumorigenic roles in multiple cancers, has an undefined function in CRC metastasis. Herein, by screening a protein homeostasis-related inhibitor library, we identified HY041004, a reported JOSD2 inhibitor, which potently suppresses β-catenin transcriptional activity. Mechanistically, JOSD2 modulates β-catenin protein abundance and functional activity via the RAS-ERK signaling cascade rather than through direct deubiquitination of β-catenin. Functional assays further demonstrated that JOSD2 inhibition via RNA interference or pharmacological inhibition significantly attenuated CRC metastasis both in vitro and in vivo. Collectively, our findings identify JOSD2 as a critical oncogenic factor that promotes β-catenin activity and validate JOSD2 as an underlying therapeutic target for metastatic CRC (mCRC).</p>

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Targeting JOSD2 degrades β-catenin to suppress colorectal cancer metastasis by disrupting RAS/ERK/β-catenin axis

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Yue Liu,
  • Shu-yu Yang,
  • Wen-han Zhang,
  • Yan-ting Liang,
  • Jun-wei Fu,
  • Jing-yu Dai,
  • Rui-lin Wu,
  • Chu-run Zheng,
  • Hao-tong Wang,
  • Yong-hao Li,
  • Run-qiu Guo,
  • Chen-ming Zeng,
  • Xiang-yu Xu,
  • Zheng-bo Song,
  • Chun-wei Xu,
  • Ji Cao,
  • Qiao-jun He,
  • Hong Zhu,
  • Tao Yuan,
  • Bo Yang

摘要

Colorectal cancer (CRC) ranks as the third most common malignancy worldwide, with metastasis representing the primary cause of mortality. Aberrant activation of the Wnt/β-catenin pathway drives epithelial‒mesenchymal transition (EMT) and CRC metastasis, making β-catenin a key therapeutic target. Josephin domain containing 2 (JOSD2), a deubiquitinase with protumorigenic roles in multiple cancers, has an undefined function in CRC metastasis. Herein, by screening a protein homeostasis-related inhibitor library, we identified HY041004, a reported JOSD2 inhibitor, which potently suppresses β-catenin transcriptional activity. Mechanistically, JOSD2 modulates β-catenin protein abundance and functional activity via the RAS-ERK signaling cascade rather than through direct deubiquitination of β-catenin. Functional assays further demonstrated that JOSD2 inhibition via RNA interference or pharmacological inhibition significantly attenuated CRC metastasis both in vitro and in vivo. Collectively, our findings identify JOSD2 as a critical oncogenic factor that promotes β-catenin activity and validate JOSD2 as an underlying therapeutic target for metastatic CRC (mCRC).