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

Ziyao Li; Ye Tian; Huafeng Zong; Xuelei Wang; Dongyang Li; Adili Keranmu; Shiyong Xin; Bowen Ye; Rong Bai; Weihua Chen; Guosheng Yang; Lin Ye; Siyan Wang

doi:10.1007/s10495-024-01953-6

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

Apoptosis. 2024 Mar 30. doi: 10.1007/s10495-024-01953-6. Online ahead of print.

Authors

Ziyao Li^#^{1

2

3}, Ye Tian^#⁴, Huafeng Zong^#⁵, Xuelei Wang¹, Dongyang Li¹, Adili Keranmu¹, Shiyong Xin¹, Bowen Ye¹, Rong Bai⁶, Weihua Chen¹, Guosheng Yang¹, Lin Ye⁷, Siyan Wang⁸

Affiliations

¹ Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
² School of Electrical Engineering of Zhengzhou University, Zhengzhou, China.
³ Center for Frontier Medical Engineering of Chiba University, Chiba, Japan.
⁴ Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China.
⁵ Department of Pathology, Dalian Friendship Hospital, Dalian, China.
⁶ Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁷ Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. ericyelin@tongji.edu.cn.
⁸ Health Management Center, Huizhou Third People's Hospital, Guangzhou Medical University, Huizhou, China. tina2000wan@163.com.

^# Contributed equally.

PMID: 38553613
DOI: 10.1007/s10495-024-01953-6

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.

Keywords: ATF3; Clear cell renal cell carcinoma; OTUD4; RBM47; Ubiquitination.

Grants and funding

202007045011/China Scholarship Council