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Circular RNA RHBDD1 regulates tumorigenicity and ferroptosis in colorectal cancer by mediating the ELAVL1/SCD mRNA interaction

Cancer Gene Therapy volume 31, pages 237–249 (2024)Cite this article

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Abstract

Circular RNAs (circRNAs) are covalently closed noncoding RNA molecules that play multiple roles in tumorigenesis and metastasis. Ferroptosis is an iron-dependent, regulated form of cell death and has emerged as a promising target for cancer treatment. However, whether and how circRNAs regulate ferroptotic cell death in colorectal cancer (CRC) remains largely unknown. Three circRNA microarrays were used to screen differentially expressed circRNAs in CRC tissues. A series of functional experiments were conducted to investigate the effects of circRNA on CRC cell proliferation, migration and ferroptosis. We found that hsa_circ_0058495 (circRHBDD1), a novel circRNA, was significantly upregulated in colorectal cancer tissues and cells. The expression levels of circRHBDD1 in serum samples were strongly associated with the advancement of CRC. Silencing of circRHBDD1 remarkably suppressed the proliferation and migration of CRC cells in vitro. Moreover, the depletion of circRHBDD1 notably increased ferroptotic cell death and enhanced RSL3-induced ferroptosis in CRC cells. Mechanistically, circRHBDD1 upregulated the expression of stearoyl-CoA desaturase (SCD), a ferroptosis suppressor mediating lipid remodelling, by enhancing the ELAVL1/SCD mRNA interaction. Finally, circRHBDD1 knockdown repressed the tumorigenesis and ferroptosis of CRC cells in vivo. In conclusion, circRHBDD1 facilitates tumour progression and obstructs ferroptosis in CRC by regulating SCD expression in an ELAVL1-dependent manner.

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Fig. 1: Upregulated circRHBDD1 is associated with CRC progression.
Fig. 2: CircRHBDD1 is a novel circRNA mainly localized in the cytoplasm.
Fig. 3: CircRHBDD1 promotes the proliferation and migration of CRC cells in vitro.
Fig. 4: CircRHBDD1 protects CRC cells against ferroptosis.
Fig. 5: CircRHBDD1 mediates the ELAVL1/SCD mRNA interaction to upregulate SCD.
Fig. 6: CircRHBDD1 exerts its oncogenic effect via SCD.
Fig. 7: CircRHBDD1 modulates tumorigenesis and ferroptosis of CRC cells in vivo.

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Data availability

All data supporting the findings of this study are available within the article, its supplementary information files, and from the corresponding author(s) upon reasonable request.

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Funding

This research was funded by the National Natural Science Foundation of China (No. 82303255), the Natural Science Foundation of Hunan Province (No. 2023JJ40894 and 2023JJ30824), and the Natural Science Foundation of Changsha City (No. kq2208361).

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, 410013, Changsha, Hunan, China

    Fei Long, Chonglei Zhong, Canbin Xie & Gui Hu

  2. Postdoctoral Station of Basic Medicine, The Third Xiangya Hospital of Central South University, 410013, Changsha, Hunan, China

    Fei Long

  3. Department of Pediatrics, The First Affiliated Hospital, University of South China, 421001, Hengyang, Hunan, China

    Qinpeng Long

  4. School of Basic Medical Science, Central South University, 410078, Changsha, Hunan, China

    Kaiyu Zhu

  5. State Key Laboratory of Oncology in South China, Sun Yat‑Sen University Cancer Center, 510060, Guangzhou, Guangdong, China

    Jia Wang

  6. Department of Gastrointestinal & Thyroid Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, 510405, Guangzhou, Guangdong, China

    Yang Yu

  7. Department of Critical Care Medicine, The Second Xiangya Hospital of Central South University, 410013, Changsha, Hunan, China

    Canbin Xie

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Contributions

Conceptualization: FL, CX and GH; methodology: FL, CZ and QL; software: QL and KZ; validation: YY and KZ; formal analysis: CZ and QL; investigation: QL and JW; resources: JW; data curation: YY and CX; writing—original draft preparation: FL; writing—review and editing: CX and GH; visualization: CX; supervision: GH; project administration: FL; funding acquisition: FL and GH. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Canbin Xie or Gui Hu.

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The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of The Third Xiangya Hospital of Central South University.

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Long, F., Zhong, C., Long, Q. et al. Circular RNA RHBDD1 regulates tumorigenicity and ferroptosis in colorectal cancer by mediating the ELAVL1/SCD mRNA interaction. Cancer Gene Ther 31, 237–249 (2024). https://doi.org/10.1038/s41417-023-00698-9

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