2. Academic Validation
  3. Linear polyubiquitylation of Gli protein regulates its protein stability and facilitates tumor growth in colorectal cancer

Linear polyubiquitylation of Gli protein regulates its protein stability and facilitates tumor growth in colorectal cancer

  • Cell Death Discov. 2024 Aug 20;10(1):369. doi: 10.1038/s41420-024-02147-4.
Junyao Cheng # 1 2,  Linlin Xu # 1 3,  Yanlu Xuan # 1 2,  Feifei Zhou # 1 4,  Aidi Huang 1 3,  Shaopeng Zeng 1,  Hailong Wang 1 5,  Yiting Wang 6,  Yuan Zhan 3,  Xiaohua Yan 7,  Shiwen Luo 1 3,  Yuan Liu 8,  Minzhang Cheng 9 10
Affiliations

Affiliations

  • 1 Center for Experimental Medicine, The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 2 Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 3 Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, Department of Pathology and Institute of Molecular Pathology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 4 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 5 Medical Innovation Centre, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 6 Department of Oncology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 7 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 8 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. liu-yuan@mail.tsinghua.edu.cn.
  • 9 Center for Experimental Medicine, The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. mzcheng@ncu.edu.cn.
  • 10 Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. mzcheng@ncu.edu.cn.
  • # Contributed equally.
PMID: 39164252 DOI: 10.1038/s41420-024-02147-4
Abstract

The linear ubiquitin chain assembly complex (LUBAC) mediates the linear ubiquitination of various proteins and is involved in NF-κB signaling and immune regulation. However, the function and mechanism of linear ubiquitination in regulating oncogenic signaling and tumor growth have remained poorly understood. Herein, we identified Gli proteins, key transcription factors in the Hedgehog (Hh) signaling pathway, as novel substrates of LUBAC. Linear ubiquitination stabilizes Gli proteins, leading to the noncanonical activation of Hh signaling in CRC cells. Furthermore, LUBAC facilitates tumor growth in CRC cells. Additionally, elevated expression of LUBAC components in CRC tissues was observed, and higher expression levels of these components correlated with poor prognosis in CRC patients. Interestingly, inhibition of LUBAC using either a small molecule agonist or RNA silencing specifically suppressed cell growth in CRC cells but had no effect on normal intestinal cells. Taken together, aberrant expression of LUBAC components activates Hh signaling noncanonically by mediating linear ubiquitination, promoting tumor growth in CRC, demonstrating the novel function of linear ubiquitination in regulating the protein stability of its substrates and highlighting the potential of targeting LUBAC as a therapeutic strategy in CRC.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122881
    LUBAC Inhibitor
    IKK