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Hsp90/C terminal Hsc70-interacting protein regulates the stability of Ikaros in acute myeloid leukemia cells

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Abstract

The stability of Ikaros family zinc finger protein 1 (Ikaros), a critical hematopoietic transcription factor, can be regulated by cereblon (CRBN) ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma. However, other stabilization mechanisms of Ikaros have yet to be elucidated. In this study, we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia (AML) cells. Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros, which is accompanied with the increased ubiquitination of Ikaros. Moreover, Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein (CHIP), which mediates the STA-9090-induced ubiquitination of Ikaros. In addition, the knockdown of Ikaros effectively inhibits the proliferation of leukemia cells, but this phenomenon could be rescued by Ikaros overexpression. Collectively, our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells, which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFA0505200), Science and Technology Committee of Shanghai (19ZR1428700, 20ZR1430600), the National Natural Science Foundation of China (81272886, 81570118, 81570112, 81700157, 81700475). We thank professor Jing Yi for her valuable suggestions and providing CHIP plasmids. We thank the excellent technique support from Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine.

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Authors and Affiliations

  1. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Meng Liu, Yanjie Ji, Huizhuang Shan, Zhihui Zou, Li Yang, Ligen Liu, Hu Lei, Yunzhao Wu, Hanzhang Xu & Yingli Wu

  2. Department of Ultrasound, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310009, China

    Jin Jin

  3. Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China

    Yang Cao

  4. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Li Zhou

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  1. Meng Liu
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Correspondence to Hanzhang Xu or Yingli Wu.

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Compliance and ethics The author(s) declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Shanghai Jiao Tong University, China). Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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Liu, M., Jin, J., Ji, Y. et al. Hsp90/C terminal Hsc70-interacting protein regulates the stability of Ikaros in acute myeloid leukemia cells. Sci. China Life Sci. 64, 1481–1490 (2021). https://doi.org/10.1007/s11427-020-1860-2

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