2. Academic Validation
  3. OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis

OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis

  • Neoplasia. 2026 Mar:73:101285. doi: 10.1016/j.neo.2026.101285.
Shuaike Qu 1,  Zhihao Liu 2,  Beibei Wang 3,  Xin Li 4,  Zhongbo Li 5,  Yingwen Gai 6,  Yanan Sun 7,  Qi Zhang 8,  Yaguang Sun 9,  Wei Pan 10,  Jian Zhu 11,  Xiaodong Tan 12
Affiliations

Affiliations

  • 1 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
  • 2 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
  • 3 Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, Heilongjiang Province, PR China. Electronic address: [email protected].
  • 4 Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address: [email protected].
  • 5 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
  • 6 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
  • 7 Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong Province, PR China. Electronic address: [email protected].
  • 8 General Surgery Ward, General Hospital of Benxi Iron and Steel co., Benxi,117000, Liaoning Province, PR China. Electronic address: [email protected].
  • 9 General Surgery Ward, General Hospital of Benxi Iron and Steel co., Benxi,117000, Liaoning Province, PR China. Electronic address: [email protected].
  • 10 General Surgery Ward, General Hospital of Benxi Iron and Steel co., Benxi,117000, Liaoning Province, PR China. Electronic address: [email protected].
  • 11 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
  • 12 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning Province, PR China. Electronic address: [email protected].
PMID: 41687501 DOI: 10.1016/j.neo.2026.101285
Abstract

The over-activation of Hippo/YAP axis was often observed in pancreatic adenocarcinoma (PAAD), while the detailed mechanism is not totally understood. Recent studies demonstrated that the ubiquitin modification, which controlled the protein stability of YAP, played important roles in Hippo signaling and PAAD progression. In order to understand the underlying link between YAP protein stability and Hippo activity in PAAD progression, we carried out GSEA bioinformatic analysis coupled with siRNA screening and identified OTUD4 as an important effector for Hippo signaling in PAAD. OTUD4, which was highly expressed in PAAD tissue, correlated with Hippo target gene expression in PAAD tissues. Depletion of OTUD4 significantly reduced the activity of Hippo/YAP axis and hampered PAAD progression. Mechanism studies revealed that OTUD4 could interact with YAP and promote YAP K48-linked poly-ubiquitination and degradation in PAAD. In conclusion, our study identified an interesting regulation mechanism between OTUD4 and Hippo signaling in PAAD, while targeting OTUD4 could be a plausible strategy for PAAD therapy. Abbreviation: OTUD4, OTU Domain-Containing Protein 4; YAP, Yes-Associated Protein; TEAD, Transcriptional Enhanced Associate Domain transcriptional factor; TCGA, The Cancer Genome Atlas; ATCC, American Type Culture Collection; DMEM, Dulbecco's Modified Eagle Medium; DUB, Deubiquitinase; GSEA, Gene Set Enrichment Analysis; NES, Normalized Enrichment Score; ECL, Enhanced Chemiluminescence; PVDF, Polyvinylidene Fluoride; PMSF, Phenyl Methane Sulfonyl Fluoride; PFA, Paraformaldehyde; Co-IP, Coimmunoprecipitation; IHC, Immunohistochemistry; CHX, Cycloheximide; IF, Immunofluorescence; GEO, Gene Expression Omnibus.

Keywords

Hippo/YAP axis; OTUD4; Pancreatic adenocarcinoma; Ubiquitin.

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