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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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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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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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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DOI: https://doi.org/10.1038/s41417-023-00698-9
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