Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells Article Swipe
Jing Ji
,
Yiming Tu
,
Lei Xu
,
Zeqiang Tao
,
Yangfan Ye
,
Jingming Hu
,
Wanzhi Cai
,
Hang Zhu
,
Qing Wu
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-4877991/v1
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-4877991/v1
Glioblastoma (GBM) is the most primary lethal brain cancer, characterized by the presence of glioblastoma stem cells (GSCs) that initiate and sustain tumor growth and induce radioresistance. Annexin A2 (ANXA2) has been reported to contribute to glioblastoma progression and impart stem cell-like properties to GSCs, however, its post-translational modifications and mechanisms in GSCs maintenance remain poorly understood. Here, we identify that USP4 is preferentially expressed by GSCs in GBM, USP4/ANXA2 supports GSCs maintenance and radioresistance. Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation. USP4 directly cleaves Lys48- and Lys63-linked polyubiquitin chains of ANXA2, with the Lys63-linked polyubiquitin chains of ANXA2 K28 mediating its Y24 phosphorylation. Moreover, K10 acetylation of ANXA2 enhances its interaction with USP4. Importantly, USP4/ANXA2 promotes GSCs maintenance and radioresistance by activating BMX-mediated STAT3 activation. H3K18 lactylation is responsible for the upregulation of USP4 in GSCs. Our studies reveal that USP4/ANXA2 plays critical roles in maintaining GSCs and therapeutic resistance, highlighting the importance of lactylation, acetylation, ubiquitination, and phosphorylation as critical post-translational modifications for USP4-mediated stabilization and activity of ANXA2.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-4877991/v1
- OA Status
- gold
- References
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All OpenAlex metadata
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- DOI
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https://doi.org/10.21203/rs.3.rs-4877991/v1Digital Object Identifier
- Title
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Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cellsWork title
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preprintOpenAlex work type
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enPrimary language
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2024Year of publication
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2024-09-05Full publication date if available
- Authors
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Jing Ji, Yiming Tu, Lei Xu, Zeqiang Tao, Yangfan Ye, Jingming Hu, Wanzhi Cai, Hang Zhu, Qing WuList of authors in order
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https://doi.org/10.21203/rs.3.rs-4877991/v1Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.21203/rs.3.rs-4877991/v1Direct OA link when available
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Radioresistance, Glioblastoma, Cancer research, Medicine, Internal medicine, Radiation therapyTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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