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KDM1A-driven RNF81 downregulation promotes gastric cancer progression via KLF4 destabilization

Oncogene volume 44, pages 3864–3878 (2025)Cite this article

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Abstract

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, especially in East Asia, with a low 5-year survival rate due to late-stage diagnosis. Identifying molecular mechanisms that regulate GC progression is critical for improving clinical outcomes. RNF81, a member of the tripartite motif (TRIM) family, has demonstrated diverse roles in various cancers. In this study, we uncover its tumor-suppressive function in GC through novel regulatory pathways. Analysis of clinical data and tissue microarrays revealed that RNF81 expression is significantly downregulated in GC tissues and positively correlates with patient survival. Mechanistically, we identified lysine demethylase KDM1A as a key repressor of RNF81 expression. KDM1A recruits transcription factor E2F1 to form a transcriptional repressor complex, reducing H3K4me1 and H3K4me2 levels at the RNF81 promoter. Functional studies showed that RNF81 stabilizes the tumor suppressor KLF4 by binding through its SPRY domain, thereby inhibiting KLF4 ubiquitination and degradation. Overexpression of RNF81 suppressed GC cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo, effects that were partially rescued by KLF4 knockdown. These findings reveal a novel KDM1A-RNF81-KLF4 regulatory axis in GC and highlight RNF81 as a potential therapeutic target for GC treatment. Targeting this pathway may offer promising strategies to improve outcomes for GC patients.

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Fig. 1: Low expression of RNF81 correlates with poor prognosis and increased malignancy in gastric cancer patients.
Fig. 2: KDM1A inhibits RNF81 expression by regulating H3K4 methylation levels on the RNF81 promoter.
Fig. 3: KDM1A-E2F1 complex transcriptionally inhibits RNF81 expression.
Fig. 4: RNF81 inhibits cell proliferation and tumor growth in gastric cancer.
Fig. 5: Identification of KLF4 as an RNF81-interacting protein and determination of their binding domains.
Fig. 6: RNF81 inhibits the ubiquitination and degradation of KLF4.
Fig. 7: RNF81 suppresses gastric cancer cell proliferation and tumor growth via KLF4.
Fig. 8: KDM1A-mediated transcriptional repression of RNF81 and its regulatory role in gastric cancer progression.

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Data availability

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

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Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 82203339), the Natural Science Foundation Project of Chongqing, China (Grant Nos. CSTB2024NSCQ-MSX0678 and CSTB2024NSCQ-MSX1201) and the Science and Technology Research Program of Chongqing Municipal Education Commission(Grant Nos. KJZD-K202402701 and KJQN202402705). Wanzhou District Science and Technology Bureau, Chongqing (Grant Nos. wzstc-20240028 and wzstc-20240022).

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Authors and Affiliations

  1. Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing Three Gorges Medical College, Chongqing, China

    Feng Wang, Po Hao, Yongli Pu, Xiao He, Qing He & Suting Jiang

  2. Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing, China

    Feng Wang, Po Hao, Yongli Pu, Xiao He, Qing He & Suting Jiang

  3. State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, China

    Hongjuan Cui

  4. Jinfeng Laboratory, Chongqing, China

    Hongjuan Cui

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  1. Feng Wang
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  5. Qing He
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Contributions

Feng Wang and Po Hao contributed to the study design, data acquisition, analysis, interpretation, in vivo studies and drafting of the manuscript; Feng Wang, Yongli Pu and Xiao He conducted analysis and in vitro studies; Qing He contributed to the conception and interpretation of the study; Hongjuan Cui contributed to the analysis and critical revision of the manuscript; Feng Wang, Hongjuan Cui and Suting Jiang contributed to the conception and interpretation of the study, acquired funding, supervised the work, and wrote the final version of the manuscript. All authors have read and approved the final version of this manuscript.

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Correspondence to Hongjuan Cui or Suting Jiang.

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All animal experiments in this study were conducted in accordance with the relevant guidelines and regulations, including institutional and national standards for the care and use of laboratory animals. Ethical approval was obtained from the Institutional Animal Care and Use Committee (IACUC) of the Three Gorges Medical College (Approval Number: TGMC-IACUC-2024-026). No human participants were involved in this study; therefore, informed consent and consent for publication are not applicable.

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Wang, F., Hao, P., Pu, Y. et al. KDM1A-driven RNF81 downregulation promotes gastric cancer progression via KLF4 destabilization. Oncogene 44, 3864–3878 (2025). https://doi.org/10.1038/s41388-025-03549-z

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