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Deacetylation of ANXA2 by SIRT2 desensitizes hepatocellular carcinoma cells to donafenib via promoting protective autophagy

Cell Death & Differentiation volume 32, pages 1630–1647 (2025) Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal forms of cancer globally. HCC cells frequently undergo macroautophagy, also known as autophagy, which can lead to tumor progression and chemotherapy resistance. Annexin A2 (ANXA2) has been identified as a potential therapeutic target in HCC and is involved in the regulation of autophagic process. Here, we for the first time showed that ANXA2 deacetylation plays a crucial role in donafenib-induced autophagy. Mechanistically, donafenib increased SIRT2 activity via triggering both SIRT2 dephosphorylation and deacetylation by respectively downregulating cyclin E/CDK and p300. Moreover, elevation of SIRT2 activity by donafenib caused ANXA2 deacetylation at K81/K206 sites, leading to a reduction of the binding between ANXA2 and mTOR, which resulted in a decrease of mTOR phosphorylation and activity, and ultimately promoted protective autophagy and donafenib insensitivity in HCC cells. Additionally, ANXA2 deacetylation at K81/K206 sites was positively correlated with poor prognosis in HCC patients. Meanwhile, we found that selective inhibition of SIRT2 increased the sensitivity of donafenib in HCC cells by strengthening ANXA2 acetylation. In summary, this study reveals that donafenib induces protective autophagy and decreases its sensitivity in HCC cells through enhancing SIRT2-mediated ANXA2 deacetylation, which suggest that targeting ANXA2 acetylation/deacetylation may be a promising strategy for improving the sensitivity of donafenib in HCC treatment.

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Fig. 1: Donafenib induces the deacetylation of ANXA2.
The alternative text for this image may have been generated using AI.
Fig. 2: Deacetylation of ANXA2 weakens its binding to mTOR.
The alternative text for this image may have been generated using AI.
Fig. 3: SIRT2 is the deacetylase of ANXA2.
The alternative text for this image may have been generated using AI.
Fig. 4: TM can sensitize the killing effect of donafenib by inhibiting SIRT2.
The alternative text for this image may have been generated using AI.
Fig. 5: Donafenib activates SIRT2 by down-regulating cyclin E/CDK2 complex mediated p-SIRT2S331 and p300 mediated Ac-SIRT2.
The alternative text for this image may have been generated using AI.
Fig. 6: Donafenib induces protective autophagy by activating SIRT2.
The alternative text for this image may have been generated using AI.
Fig. 7: Inhibiting SIRT2-mediated deacetylation of ANXA2 sensitizes hepatocellular carcinoma cells to donafenib.
The alternative text for this image may have been generated using AI.
Fig. 8: The degree of ANXA2 acetylation in patients with HCC is related to poor prognosis.
The alternative text for this image may have been generated using AI.
Fig. 9: Schematic diagram of ANXA2 acetylation enhancing sensitivity to donafenib.
The alternative text for this image may have been generated using AI.

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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Funding

This study was supported by the National Natural Science Foundation of China (82073300, 32300626, 82273114, and 82273112), Chongqing Natural Science Foundation (CSTB2022NSCQ-LZX0018 and CSTB2023NSCQ-MSX0651), and Youth Training Program of Army Medical University (2022XQN05).

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Author notes

  1. These authors contributed equally: Liangbo Sun, Meng He, Dong Liu, Meihua Shan, Lingxi Chen.

Authors and Affiliations

  1. Department of Clinical Biochemisty, Army Medical University, Chongqing, 400038, China

    Liangbo Sun, Meng He, Dong Liu, Meihua Shan, Mingzhen Yang, Yang Zhang, Li Xiang, An Chen & Jiqin Lian

  2. Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China

    Lingxi Chen, Tao Li, Yan Zhang & Fengtian He

  3. Department of Educational College, Chongqing Normal University, Chongqing, 400047, China

    Xufang Dai

  4. Institute of Digital Medicine, Biomedical Engineering College, Army Medical University, Chongqing, 400038, China

    Jie Yao

  5. Department of Vascular Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Yingxue Hao

  6. Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Haojun Xiong

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Contributions

Study design: LBS, HJX and JQL; Data acquisition, analysis, and interpretation: LBS, MH, DL, MHS, and LXC; Investigation: LBS, MHS, DL, MZY, XFD, YZ, JY, TL, LX, AC and YZ; Paper drafting and revising: LBS, YXH, HJX, FTH and JQL; All authors approved the final version of the paper.

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Correspondence to Yingxue Hao, Fengtian He, Haojun Xiong or Jiqin Lian.

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The collection of specimens and animal handling for the study have been reviewed and approved by the Clinical Research Ethics Committee of the Shanghai Outdo Biotech Company and the Ethics Committee of the Army Medical University. All methods were performed in accordance with the relevant guidelines and regulations.

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Sun, L., He, M., Liu, D. et al. Deacetylation of ANXA2 by SIRT2 desensitizes hepatocellular carcinoma cells to donafenib via promoting protective autophagy. Cell Death Differ 32, 1630–1647 (2025). https://doi.org/10.1038/s41418-025-01499-3

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