2. Academic Validation
  3. A novel polypeptide encoded by circSPIRE1 promotes prostate cancer proliferation and migration by restraining the ubiquitin-dependent degradation of LRP5

A novel polypeptide encoded by circSPIRE1 promotes prostate cancer proliferation and migration by restraining the ubiquitin-dependent degradation of LRP5

  • J Exp Clin Cancer Res. 2025 Jul 25;44(1):218. doi: 10.1186/s13046-025-03467-8.
Jintao Hu # 1 2 3,  Juanyi Shi # 1 2 3,  Junjie Wang # 1 2 3,  Yunfei Xiao # 1 2 3,  Degeng Kong 1 2 3,  Mingchao Gao 1 2 3,  Tianlong Luo 1 2 3,  Shizhong Xu 1 2 3,  Zhihan Yuan 1 2 3,  Xinyi Ma 4,  Xueseng Dong 5,  Jingang Huang 6,  Cheng Liu 7 8 9 10,  Kewei Xu 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China.
  • 3 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, China.
  • 4 Sun Yat-sen University School of Medicine, Sun Yat-sen University, Shenzhen, 518000, Guangdong, China.
  • 5 The Vancouver Prostate Centre, Department of Urologic Sciences, Vancouver General Hospital, The University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H3Z6, Canada.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. huangjg35@mail.sysu.edu.cn.
  • 7 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. liuch278@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. liuch278@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, China. liuch278@mail.sysu.edu.cn.
  • 10 Department of Urology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China. liuch278@mail.sysu.edu.cn.
  • 11 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. xukewei@mail.sysu.edu.cn.
  • 12 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. xukewei@mail.sysu.edu.cn.
  • 13 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, China. xukewei@mail.sysu.edu.cn.
  • 14 Sun Yat-sen University School of Medicine, Sun Yat-sen University, Shenzhen, 518000, Guangdong, China. xukewei@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40713830 DOI: 10.1186/s13046-025-03467-8
Abstract

Background: Circular RNAs (circRNAs) are increasingly implicated in tumor progression, but the roles of protein-coding circRNAs remain largely unexplored. This study characterizes a novel circRNA-encoded protein, rtSPIRE1, and investigates its mechanistic role in prostate Cancer proliferation and migration, as well as its diagnostic and therapeutic potential.

Methods: RNA microarray identified circSPIRE1 in prostate Cancer tissues. The translation of rtSPIRE1 was confirmed by polysome profiling analysis, Western blotting, and mass spectrometry. Expression levels of circSPIRE1 and rtSPIRE1 were analyzed via qPCR, FISH, and immunohistochemistry. Gain- and loss-of-function assays were performed to evaluate their effects on cell proliferation and migration. Mechanistic studies were conducted using RNA pulldown, RIP, co-immunoprecipitation, and molecular docking.

Results: We identified rtSPIRE1, a novel protein encoded by circSPIRE1 through rolling circle translation, whose expression is regulated by hnRNPA1-mediated symmetric dimethylation. Both circSPIRE1 and rtSPIRE1 were significantly upregulated in prostate Cancer tissues and cell lines, with higher expression levels correlating with worse prognosis. Mechanistically, rtSPIRE1 stabilized LRP5 by inhibiting its ubiquitination and degradation, leading to sustained activation of the PI3K/Akt signaling pathway, which ultimately promotes prostate Cancer cell proliferation and migration.

Conclusions: Our findings identify rtSPIRE1 as a critical oncogenic protein encoded by circSPIRE1 through rolling circle translation, with its expression regulated by hnRNPA1-mediated symmetric dimethylation. Mechanistically, rtSPIRE1 promotes proliferation and migration by stabilizing LRP5 and activating the PI3K/Akt signaling pathway. Together, circSPIRE1 and rtSPIRE1 represent promising diagnostic biomarkers and therapeutic targets for prostate Cancer.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13046-025-03467-8.

Keywords

LRP5; Migration; Peptide; Proliferation; Prostate cancer; Rolling circle translation; Ubiquitination; circSPIRE1; hnRNPA1.

Figures
Products
Inhibitors & Agonists
Other Products