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Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells

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Abstract

Dysregulation of deubiquitination contributes to various diseases, including cancer, and aberrant expression of deubiquitinating enzymes is involved in carcinoma progression. As a member of the ovarian tumor (OTU) deubiquitinases, OTUD4 is considered a tumor suppressor in many kinds of malignancies. The biological characteristics and mechanisms of OTUD4 in clear cell renal cell carcinoma (ccRCC) remain unclear. The downregulation of OTUD4 in ccRCC was confirmed based on the TCGA database and a validation cohort of 30-paired ccRCC and para-carcinoma samples. Moreover, OTUD4 expression was detected by immunohistochemistry in 50 cases of ccRCC tissues, and patients with lower levels of OTUD4 showed larger tumor size (p = 0.015). TCGA data revealed that patients with high expression of OTUD4 had a longer overall survival rate. In vitro and in vivo studies revealed that downregulation of OTUD4 was essential for tumor cell growth and metastasis in ccRCC, and OTUD4 overexpression inhibited these malignant phenotypes. We further found that OTUD4 sensitized ccRCC cells to Erastin-induced ferroptosis, and ferrostain-1 inhibited OTUD4-induced ferroptotic cell death. Mechanistic studies indicated that OTUD4 functioned as an anti-proliferative and anti-metastasic factor through the regulation of RNA-binding protein 47 (RBM47)-mediated activating transcription factor 3 (ATF3). OTUD4 directly interacted with RBM47 and promoted its stability via deubiquitination events. RBM47 was critical in ccRCC progression by regulating ATF3 mRNA stability, thereby promoting ATF3-mediated ferroptosis. RBM47 interference abolished the suppressive role of OTUD4 overexpression in ccRCC. Our findings provide mechanistic insight into OTUD4 of ccRCC progression and indicate a novel critical pathway OTUD4/RBM47/ATF3 may serve as a potential therapeutic pathway for ccRCC.

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Data Availability

The datasets used during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the China Scholarship Council (No. 202007045011).

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  1. Ziyao Li, Ye Tian and Huafeng Zong are contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Ziyao Li, Xuelei Wang, Dongyang Li, Adili Keranmu, Shiyong Xin, Bowen Ye, Weihua Chen, Guosheng Yang & Lin Ye

  2. School of Electrical Engineering of Zhengzhou University, Zhengzhou, China

    Ziyao Li

  3. Center for Frontier Medical Engineering of Chiba University, Chiba, Japan

    Ziyao Li

  4. Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, China

    Ye Tian

  5. Department of Pathology, Dalian Friendship Hospital, Dalian, China

    Huafeng Zong

  6. Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Rong Bai

  7. Health Management Center, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, China

    Siyan Wang

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  1. Ziyao Li
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Contributions

Lin Ye and Siyan Wang designed the experiments. Ziyao Li, Ye Tian, and Huafeng Zong analyzed the data and prepared the manuscript. Material preparation, data collection and analysis were performed by Xuelei Wang, Dongyang Li, Adili Keranmu, Shiyong Xin, Bowen Ye, Rong Bai, Weihua Chen, and Guosheng Yang. Guosheng Yang and Lin Ye provided technical support. All authors read and approved the final paper.

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Correspondence to Lin Ye or Siyan Wang.

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Li, Z., Tian, Y., Zong, H. et al. Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01953-6

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