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Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells

Cell Death & Differentiation volume 32, pages 1648–1663 (2025)Cite this article

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Abstract

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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Fig. 1: USP4 is preferentially expressed by GSCs in GBM.
Fig. 2: USP4 is required for survival, self-renewal and sensitivity to ionizing radiation (IR) of GSCs.
Fig. 3: USP4 interacts with ANXA2 and stabilizes its protein.
Fig. 4: USP4 directly cleaves Lys 48-, Lys 63-polyubiquitin chain on ANXA2.
Fig. 5: USP4 regulates Y24 phosphorylation of ANXA2 by cleaving Lys63-polyubiquitin chain on ANXA2 K28.
Fig. 6: K10 acetylation of ANXA2 increases its interaction with USP4.
Fig. 7: USP4/ANXA2 disrupts BMX-mediated STAT3 activation in GSCs.
Fig. 8: Lactic-acid-induced USP4 upregulation in GBM via H3K18 histone lactylation.

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All data associated with this study are present in the paper or the Supplementary Materials.

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Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 82120108018 to JJ, 82303835 to YT], the National Key Research and Development Program of China [grant number 2021YFA1101802-2 to JJ], the Priority Academic Program Development of Jiangsu Higher Education Institutions [grant numbers JX10231803, JX10231804 to JJ], Xinjiang Uygur Autonomous Region Tianshan Innovation Team Plan Item [grant numbers 2024D14012 to JJ], the Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars [grant number BK20220727 to YT], the China Postdoctoral Science Foundation [grant number 2021M701495 to YT].

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  1. These authors contributed equally: Yiming Tu, Lei Xu, Guoqiang Fu.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Yiming Tu, Lei Xu, Guoqiang Fu, Jichen Wang, Pengfei Xia, Zeqiang Tao, Yangfan Ye, Jingming Hu, Wanzhi Cai, Hang Zhu, Qing Wu & Jing Ji

  2. Department of Neurosurgery, The Affiliated Kizilsu Kirghiz Autonomous Prefecture People’s Hospital of Nanjing Medical University, Artux, Xinjiang, China

    Jing Ji

  3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China

    Jing Ji

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Contributions

JJ and YT conceived and designed the study and interpreted results. YT, LX, GF, JW, PX, ZT, YY, JH, WC, HZ, and QW performed most experiments. JJ and YT wrote the manuscript with comments from all authors.

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Correspondence to Jing Ji.

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This study involved animal experiments that were approved by the Ethics Review Committee of Nanjing Medical University. All methods were performed in accordance with the relevant guidelines and regulations.

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Tu, Y., Xu, L., Fu, G. et al. Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells. Cell Death Differ 32, 1648–1663 (2025). https://doi.org/10.1038/s41418-025-01494-8

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