2. Academic Validation
  3. VCPIP1 facilitates pancreatic adenocarcinoma progression via Hippo/YAP signaling

VCPIP1 facilitates pancreatic adenocarcinoma progression via Hippo/YAP signaling

  • Cell Death Dis. 2025 May 28;16(1):422. doi: 10.1038/s41419-025-07746-2.
Zhihao Liu # 1,  Chenmiao Zhang # 2,  Yingwen Gai # 1,  Peng Su # 3,  Beibei Wang 4,  Peng Liu 1,  Limin Wang 5,  Yue Lin 5,  Jian Zhu 6,  Xiaodong Tan 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, China.
  • 2 Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, PR China.
  • 3 Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, PR China.
  • 4 Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, Heilongjiang, PR China.
  • 5 Department of General Surgery, Tiemei General Hospital of Liaoning Province Health Industry Group, Tieling, 112000, Liaoning, PR China.
  • 6 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, China. zhujian1204@yahoo.com.
  • 7 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, China. tanxdcmu@163.com.
  • # Contributed equally.
PMID: 40436845 DOI: 10.1038/s41419-025-07746-2
Abstract

Dysregulation of Hippo signaling is observed in pancreatic adenocarcinoma (PAAD). Moreover, overactivation of YAP is crucial for tumor progression. Although the inhibitory phospho-cascade is functional, the reason for YAP hyperactivation in PAAD remains unclear. Recent studies have revealed that the ubiquitin modification of YAP also plays an important role in the Hippo/YAP axis and Cancer progression. To gain a better understanding of the potential mechanisms underlying the ubiquitination and deubiquitination of YAP, we carried out siRNA screening for critical deubiquitinases in PAAD. By using a Deubiquitinase (DUB) library, we identified valosin-containing protein-interacting protein 1 (VCPIP1) as an important effector of YAP function and PAAD progression. Inhibition of VCPIP1 hampered PAAD progression via Hippo signaling. Clinical data revealed that VCPIP1 was elevated in PAAD and correlated with poor survival in PAAD patients. Biochemical assays demonstrated that VCPIP1 interacted with YAP, inhibiting K48-linked polyubiquitination and thereby increasing YAP stability. YAP directly binds to the VCPIP1 promoter region, enhancing its transcription in PAAD. Our study revealed a forward feedback loop between VCPIP1 and Hippo signaling in PAAD, indicating that VCPIP1 is a potential therapeutic drug target in PAAD.

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