USP25 deubiquitinates cytosolic METTL3 to impede glioma proliferation via an m6A-independent pathway
METTL3 exhibits distinct tumorigenic roles in the nucleus and cytoplasm, but whether its post-transcriptional modifications vary by subcellular localization remains unclear. Here, we identify METTL3 as a substrate of the deubiquitinase USP25, which stabilizes cytosolic METTL3 by cleaving its K48-linked polyubiquitin chains, preventing proteasomal degradation, without affecting nuclear METTL3 or global m6A abundance. The analysis of clinical glioma samples reveals a positive correlation between USP25 and METTL3 protein levels, with both significantly upregulated in high-grade glioma. Moreover, USP25 enhances EGFR expression through cytosolic METTL3, driving glioma progression. Our findings highlight that METTL3 undergoes distinct post-translational modifications based on its subcellular localization, providing new insights into the spatial regulation of METTL3 in gliomas.
Authors
- Wujie Zhao (ORCID: https://orcid.org/0000-0002-7244-8619)
- Sifang Chen (ORCID: https://orcid.org/0000-0001-5198-1361)
- Liwei Zhou
- Ya‐Hui Hu (ORCID: https://orcid.org/0000-0002-2587-7779)
- Jiawei He (ORCID: https://orcid.org/0000-0003-1636-1823)
- Shouren Chen (ORCID: https://orcid.org/0000-0001-6902-6952)
- Zhenwei Lu (ORCID: https://orcid.org/0000-0001-9614-3038)
- Hanwen Lu (ORCID: https://orcid.org/0000-0003-1552-116X)
- Wanhong Han
- Xin Gao (ORCID: https://orcid.org/0000-0003-1864-7796)
- Jianhua Yu
- Zhanxiang Wang (ORCID: https://orcid.org/0000-0003-0405-6194)
- Xinwen Liao
- Bingchang Zhang (ORCID: https://orcid.org/0000-0002-7655-7257)
- Yuanyuan Xie (ORCID: https://orcid.org/0000-0003-3746-2076)
- Yaya Zhang (ORCID: https://orcid.org/0000-0003-3389-5333)
- Xinguang Qiu (ORCID: https://orcid.org/0000-0001-9574-9812)
- Xiyao Liu (ORCID: https://orcid.org/0000-0002-0812-9138)
- Wentao Zhao (ORCID: https://orcid.org/0000-0002-4125-239X)
- Wenhua Li (ORCID: https://orcid.org/0000-0003-0257-7252)
- Guowei Tan (ORCID: https://orcid.org/0000-0003-4174-0382)
- Yanyan Geng (ORCID: https://orcid.org/0009-0006-5046-8527)
Institutions
- Fujian Medical University (CN)
- Xiamen University (CN)
- First Affiliated Hospital of Xiamen University (CN)
- Zhangzhou Municipal Hospital of Fujian Province (CN)
- First Affiliated Hospital of Fujian Medical University (CN)
- Xiamen Chang Gung Hospital (CN)
- Xiamen Maternal and Child Health Hospital (CN)
Publication Details
- Journal
- iScience
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1016/j.isci.2025.113918
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00