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USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer

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Abstract

The ectopic expression of ubiquitin-specific peptidase 21 (USP21) is common in different types of cancer. However, its relationship with radio-sensitivity in cervical cancer (CC) remains unclear. In this study, we aimed to uncover the effect of USP21 on CC radio-resistance and its underlying mechanism. Our results showed that the expression of USP21 was markedly increased in CC tissues of radio-resistant patients and CC cells treated with radiation. Besides, knockdown of USP21 restrained the survival fractions, and facilitated apoptosis of CC cells in the absence or presence of radiation. Additionally, USP21 in combination with FOXM1 regulated the stability and ubiquitination of FOXM1. However, FOXM1 reversed the effects of USP21 knockdown on the radio-resistance of CC cells. Furthermore, FOXM1 knockdown activated the Hippo pathway by inhibiting the nuclear translocation of Yes-associated protein 1 (YAP1), and FOXM1 knockdown attenuated the radio-resistance of CC cells via inhibiting the Hippo–YAP1 pathway. USP21 activated the Hippo pathway by mediating FOXM1. Knockdown of USP21 enhanced the radio-sensitivity of CC cells in vivo. In summary, USP21 contributed to the radio-resistance of CC cells via FOXM1/Hippo signaling, and may serve as a promising target for radio-sensitizers in the radiotherapy of CC.

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Availability of data and materials

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

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Author notes

  1. Zhengliang Li and Xiaojing Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Radiotherapy, Yantaishan Hospital, No. 10087 Science and Technology Avenue, Laishan District, Yantai, Shandong, China

    Zhengliang Li, Shuliang Zhao & Guoxiang Jiang

  2. Department of Traditional Chinese Medicine, Yantai Center for Food and Drug Control, Yantai, Shandong, China

    Xiaojing Liu

  3. Department of Pharmacology and Toxicology, Yantai Center for Food and Drug Control, Yantai, Shandong, China

    Haizhou Yu

  4. School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China

    Shaoping Wang

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  1. Zhengliang Li
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Contributions

ZLL, XJL, and GXJ made crucial contribution to the conception of this study. ZLL, HZY, and SPW carried out all of the experiments. SLZ prepared the first draft of this manuscript. GXJ agreed to the final design of this work and revised the manuscript critically. XJL performed cell culture and western blotting. All authors have read and approved the final manuscript.

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Correspondence to Guoxiang Jiang.

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The authors declare that they have no conflict of interest.

Ethical approval

The use of human CC tissues was approved by the Ethics Committee of Yantaishan Hospital (approval No.: 2020016), and the experimental procedures were performed in accordance with the guidelines stipulated in the World Medical Association Declaration of Helsinki. Signed informed consent was obtained from all patients before research initiation. All animal experimental procedures were reviewed and approved by the Ethics Committee of Yantaishan Hospital, and the experimental procedures were performed in accordance with the Guidelines of the National Regulation of China for Care and Use of Laboratory Animals.

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Li, Z., Liu, X., Yu, H. et al. USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer. Human Cell 35, 333–347 (2022). https://doi.org/10.1007/s13577-021-00650-9

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  • DOI: https://doi.org/10.1007/s13577-021-00650-9

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