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USP25 deubiquitinates cytosolic METTL3 to impede glioma proliferation via an m6A-independent pathway
Bingchang Zhang1, Wanhong Han1,2, Xin Gao1
1Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Abstract:
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.
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