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USF2 promotes autophagy and proliferation in chronic lymphocytic leukemia by inhibiting STUB1-induced NFAT5 ubiquitination

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Abstract

Chronic lymphocytic leukemia (CLL) mainly affects the health of older adults and is difficult to cure. Upstream stimulatory factor 2 (USF2) has been implicated in several diseases and conditions including cancers. However, the effect of USF2 on CLL has not been elucidated. To investigate the effect of USP2 on proliferation and autophagy of CLL, and to explore the underlying mechanism. The mRNA of USF2 and STIP1 homology and U-Box containing protein 1 (STUB1) was analyzed using qRT-PCR. Western blots were used to evaluate the expression level of USF2, LC3II, Beclin-1, P62, STUB1, and NFAT5. The cell proliferation was evaluated using CCK-8 and EdU assays. The cell apoptosis was evaluated using flow cytometry. Indirect fluorescent assay (IFA) was performed to analyze LC3 signal. Nuclear factor of activated T-cells 5 (NFAT5) ubiquitination was detected using immunoprecipitation (IP) assay. The CLL progression was evaluated in xenotransplantation model of nude mice. USF2 was highly expressed in CLL tissues and cell lines. USF2 knockdown suppressed the cell viability and EdU incorporation, while promoting cell apoptosis. Meanwhile, USF2 knockdown reduced the level of LC3II and Beclin-1, but increased P62, illustrating USF2 knockdown inhibiting autophagy. USF2 induced NFAT5 ubiquitination and promoted NFAT5 protein level via repressing STUB1. The downregulation of USF2 weakened CLL progression in xenotransplantation model of nude mice. CLL survival and autophagy was dependent on highly expressed USF2 which promoted the expression and ubiquitination of NFAT5 through inhibiting the transcription of STUB1, which makes USF2 a promising therapeutic candidate for CLL treatment.

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Data availability

All data generated or analyzed during this study are included in this published article.

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Hematology, Affiliated Hospital of Guilin Medical University, No. 15, Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China

    Beili Chen, Shujuan Xu, Fang Jiang, Yuwei Nie, Ailin Tang & Qin Zhou

  2. Department of Oncology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China

    Yanyi Zhao

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  1. Beili Chen
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Contributions

Beili Chen and Yanyi Zhao designed the study, completed the experiment, and supervised the data collection; Shujuan Xu analyzed the data and interpreted the data; Fang Jiang, Yuwei Nie, Ailin Tang, and Qin Zhou prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

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Correspondence to Beili Chen.

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Chen, B., Zhao, Y., Xu, S. et al. USF2 promotes autophagy and proliferation in chronic lymphocytic leukemia by inhibiting STUB1-induced NFAT5 ubiquitination. Ann Hematol 103, 533–544 (2024). https://doi.org/10.1007/s00277-023-05522-w

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  • DOI: https://doi.org/10.1007/s00277-023-05522-w

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