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Circular RNA RHBDD1 regulates tumorigenicity and ferroptosis in colorectal cancer by mediating the ELAVL1/SCD mRNA
Fei Long1,2, Chonglei Zhong1, Qinpeng Long3
1Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, 410013, Changsha, Hunan, China.
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.
Insights
Circular RNAs (circRNAs) promote colorectal cancer (CRC) progression by inhibiting ferroptosis. The novel circRHBDD1 enhances tumor growth and metastasis by suppressing iron-dependent cell death via SCD regulation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Circular RNAs (circRNAs) are noncoding RNA molecules implicated in cancer development.
- Ferroptosis, an iron-dependent cell death, is a potential cancer therapeutic target.
- The role of circRNAs in regulating ferroptosis in colorectal cancer (CRC) is not well understood.
Purpose of the Study:
- To investigate the role of circRNAs in regulating ferroptosis in colorectal cancer.
- To identify specific circRNAs involved in CRC progression and ferroptosis.
- To elucidate the molecular mechanisms by which circRNAs influence ferroptosis in CRC.
Main Methods:
- CircRNA microarrays for differential expression screening in CRC tissues.
- In vitro functional assays (cell proliferation, migration, ferroptosis assays).
- In vivo studies (tumorigenesis and ferroptosis in a mouse model).
- Mechanistic studies involving RNA-protein interactions and gene expression analysis.
Main Results:
- Hsa_circ_0058495 (circRHBDD1) was significantly upregulated in CRC tissues, cells, and serum, correlating with disease advancement.
- circRHBDD1 silencing suppressed CRC cell proliferation and migration in vitro.
- Depletion of circRHBDD1 increased ferroptotic cell death and enhanced RSL3-induced ferroptosis.
- circRHBDD1 upregulates stearoyl-CoA desaturase (SCD) expression by enhancing the ELAVL1/SCD mRNA interaction, thereby suppressing ferroptosis.
- circRHBDD1 knockdown repressed CRC tumorigenesis and ferroptosis in vivo.
Conclusions:
- circRHBDD1 acts as an oncogene in colorectal cancer by promoting tumor progression.
- circRHBDD1 obstructs ferroptosis in CRC through the ELAVL1-dependent regulation of SCD expression.
- circRHBDD1 is a potential diagnostic biomarker and therapeutic target for colorectal cancer.
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