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HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285

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Abstract

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

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Data availability

All data from UCSC Xena database are publicly available. The main data from this manuscript are available from the corresponding author on reasonable request.

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Acknowledgements

We also thank the UCSC Xena database for the contribution in our study.

Funding

This research was supported by grants from the National Natural Science Foundation of China (Grant Number 81772280), Key Technology Innovation Special of Key Industries of the Chongqing Science and Technology Bureau (Grant Number csct2022ycjh-bgzxm0034), and Chongqing Graduate Research Innovation Project Funding (CYS21229).

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Authors and Affiliations

  1. Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160, China

    Ziwei Zhou, Xuan Chu, Peng Wan, Wenran Dan, Xin Shao, Shuyu Chen, Zhonghui Zhang, Yang Lu & Beizhong Liu

  2. Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China

    Liang Zhong & Beizhong Liu

Authors
  1. Ziwei Zhou
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  2. Liang Zhong
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  3. Xuan Chu
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  4. Peng Wan
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  5. Wenran Dan
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  6. Xin Shao
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  7. Shuyu Chen
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  8. Zhonghui Zhang
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  9. Yang Lu
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Contributions

Conceptualization: ZZ and LZ; investigation: ZZ, XC, and WD; resources: ZZ and PW; data curation: ZZ, XS, and SC; writing—original draft: ZZ; writing—review & editing: ZZ and YL; supervision: BL; project administration: BL.

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Correspondence to Beizhong Liu.

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Zhou, Z., Zhong, L., Chu, X. et al. HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285. Med Oncol 40, 325 (2023). https://doi.org/10.1007/s12032-023-02196-2

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