ORIGINAL RESEARCH article
Front. Oncol.
Sec. Gastrointestinal Cancers: Hepato Pancreatic Biliary Cancers
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1616968
This article is part of the Research TopicInterplay between Environmental Drivers and Genetic or Epigenetic Predispositions on Gastrointestinal Cancer EvolutionView all 3 articles
Hypoxia Promotes Pancreatic Adenocarcinoma Progression by Stabilizing ID1 via TRIM21 Suppression
Provisionally accepted
Rui Cheng
Yuanjun TangXuedi CaoZhanya HuangYunyun GuoRenjing Jin
Yan Wang
Yang Liu
Lixiang Xue*
Yuqing Wang*- Peking University Third Hospital, Haidian, China
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Hypoxia is a hallmark of the pancreatic adenocarcinoma (PAAD) microenvironment and plays a critical role in driving tumor progression. In PAAD, the Inhibitor of DNA binding 1 (ID1) is markedly overexpressed and contributes significantly to tumor invasion, migration, and proliferation. However, the mechanisms underlying ID1 upregulation remain poorly understood. In this study, we demonstrate that hypoxia enhances the aggressiveness of PAAD by inducing ID1 expression. Mechanistically, hypoxia stabilizes ID1 by attenuating its ubiquitin-mediated degradation. We identify the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) as a key regulator of ID1 turnover under normoxic conditions. Hypoxic stress markedly suppresses TRIM21 expression, resulting in reduced ID1 ubiquitination and subsequent protein accumulation. Functionally, hypoxia-induced stabilization of ID1 promotes cancer cell invasion and proliferation, thereby accelerating PAAD progression. Notably, TRIM21 knockdown abrogates the oncogenic effects of ID1 under hypoxic conditions, eliminating the differential growth advantage conferred by ID1 between hypoxia and normoxia. Collectively, our findings reveal a novel hypoxia–TRIM21–ID1 regulatory axis that drives PAAD progression and highlight this pathway as a promising therapeutic target.
Keywords: hypoxia, Pancreatic adenocarcinoma, Id1, TRIM21, Ubiquitination
Received: 23 Apr 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Cheng, Tang, Cao, Huang, Guo, Jin, Wang, Liu, Xue and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lixiang Xue, Peking University Third Hospital, Haidian, China
Yuqing Wang, Peking University Third Hospital, Haidian, China
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