Unlocking hepatocellular carcinoma aggression - STAMBPL1-mediated TRAF2 deubiquitination activates WNT/PI3K/NF-kb signaling pathway

Sep 21, 2026

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STAM Binding Protein Like 1 (STAMBPL1) acts as a deubiquitinase (DUB), but its contribution to hepatocellular carcinoma (HCC) remained unclear. STAMBPL1 is upregulated in HCC and correlates with poor prognosis. Mechanistically, STAMBPL1 promotes HCC cell proliferation and metastasis by interacting with TRAF2 and stabilizing it through K63-residue deubiquitination. Stabilized TRAF2 drives nuclear translocation of P65 and activates the WNT/PI3K/NF-kB signaling pathway. Targeting the STAMBPL1 251–436 region to the TRAF2 294–496 region enables DUB activity and removal of ubiquitin on TRAF2. These findings support STAMBPL1 as a biomarker and therapeutic target for HCC.

LanguageEnglish

CategoryResearch & Report

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Reading Time55 min

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Abstract

Introduction

Deubiquitination and DUBs in cancer

Wang et al. Biology Direct (2024) 19:18 [https://doi.org/10.1186/s13062-024-00460-7](https://doi.org/10.1186/s13062-024-00460-7) Biology Direct RESEARCH Open Access Unlocking hepatocellular carcinoma aggression: STAMBPL1-mediated TRAF2 deubiquitination activates WNT/PI3K/NF-kb signaling pathway Zhihuai Wang1,2†, Yinjie Zhang1,2†, Yuhang Shen1,2†, Haiyang Zhou1,2, Yuan Gao2, Chunfu Zhu1,2* and Xihu Qin1,2* Abstract STAM Binding Protein Like 1 (STAMBPL1), functions as a deubiquitinase (DUB) and plays a significant role in various types of cancers. However, its effect as a DUB participating in the HCC tumorigenesis and progression still unknown. In the study, the upregulation and strong prognosis value of STAMBPL1 were identified in HCC patients. Functionally, STAMBPL1 significantly promoted HCC cells proliferation and metastasis, and it interacts with TRAF2 and stabilize it via the deubiquitination at the K63 residue. The TRAF2 upregulation stabilized by STAMBPL1 overexpression transfers of P65 protein into the nucleus and activates the WNT/PI3K/ NF-kb signaling pathway. The 251–436 sites of STAMBPL1 particularly interact with the 294–496 sites ofTRAF2, thereby exerting the function of DUB and removing the ubiquitin molecules attached toTRAF2 . Our research unveiled a new function of STAMBPL1 in mediating TRAF2 deubiquitination and stabilization, thereby activating the WNT/PI3K/NF-kb signaling pathway, suggesting its potential as a novel biomarker and therapeutic target for HCC. Introduction Hepatocellular carcinoma (HCC) is one of the most lethal malignancies around the world. Most HCC patients were diagnosed in later period because of lacking reliable diagnosed biomarkers [1]. Although there are a few of therapeutic methods such as surgery, targeted therapy, immunotherapy, and radiotherapy, the overall survival †Zhihuai Wang, Yinjie Zhang, andYuhang Shen have contributed equally to this article. *Correspondence: Chunfu Zhu [zcfmlm@163.com](zcfmlm@163.com)[ ](zcfmlm@163.com)Xihu Qin [zcfmlm@njmu.edu.cn](zcfmlm@njmu.edu.cn) 1 Nanjing Medical University, Nanjing 211166, China 2 Department of General Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou 213000, China (OS) and progression free survival (PFS) rates of HCC patients [2]. Thus, it is necessary to explore novel diagnosed biomarkers and therapeutic targets to improve the diagnosis and treatment of HCC patients. Deubiquitination is a process that removes ubiquitin from proteins, reversing the ubiquitination process that typically targets proteins for degradation by the proteasome [3] . This process is mediated by deubiquitinating enzymes (DUBs), which can have various roles in cellular processes, including cell cycle regulation [4], DNA repair [5], and signal transduction [6, 7] . Deubiquitination has been shown to play a significant role in the progression and treatment of cancer progression [8] . Specifically, in prostate cancer, the deubiquitinase USP22 has been found to be overexpressed with disease progression and is associated with poor prognosis, making it a potential therapeutic target [9] . USP11 © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of

FAQs

What role does STAMBPL1 play in hepatocellular carcinoma?

STAMBPL1 functions as a deubiquitinase and is upregulated in HCC, where it promotes cell proliferation and metastasis.

How does STAMBPL1 regulate TRAF2?

STAMBPL1 interacts with TRAF2 and stabilizes it by deubiquitinating TRAF2 at the K63 residue.

Which signaling pathway is activated downstream of the STAMBPL1–TRAF2 axis?

STAMBPL1-mediated TRAF2 stabilization leads to P65 nuclear translocation and activates the WNT/PI3K/NF-kB signaling pathway.

Sep 21, 2026

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