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m6A-modified circFNDC3B inhibits colorectal cancer stemness and metastasis via RNF41-dependent ASB6 degradation
Wei Zeng1,2, Jin-Feng Zhu3, Jian Guo1
1Department of Oncology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong Province, P.R. China.
Abstract:
Colorectal cancer (CRC) is the third most frequently diagnosed cancer with unfavorable clinical outcomes worldwide. circFNDC3B plays as a tumor suppressor in CRC, however, the mechanism of circFNDC3B in CRC remains ambiguous. The stem-like properties of CRC cells were detected by the evaluation of stemness markers, sphere formation assay and flow cytometry. qRT-PCR, FISH, IHC, and western blotting assessed the expression and localization of circFNDC3B, RNF41, ASB6, and stemness markers in CRC. The metastatic capabilities of CRC cells were examined by wound healing and Transwell assays, as well as in vivo liver metastasis model. Bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down assay and co-IP were used to detect the associations among circFNDC3B, FXR2, RNF41, and ASB6. Downregulated circFNDC3B was associated with unfavorite survival in CRC patients, and circFNDC3B overexpression suppressed CRC stemness and metastasis. Mechanistically, studies revealed that YTHDC1 facilitated cytoplasmic translocation of m6A-modified circFNDC3B, and circFNDC3B enhanced RNF41 mRNA stability and expression via binding to FXR2. circFNDC3B promoted ASB6 degradation through RNF41-mediated ubiquitination. Functional studies showed that silencing of RNF41 counteracted circFNDC3B-suppressed CRC stemness and metastasis, and ASB6 overexpression reversed circFNDC3B- or RNF41-mediated regulation of CRC stemness and metastasis. Elevated ASB6 was positively correlated with unfavorite survival in CRC patients. In vivo experiments further showed that circFNDC3B or RNF41 overexpression repressed tumor growth, stemness and liver metastasis via modulating ASB6. Taken together, m6A-modified circFNDC3B inhibited CRC stemness and metastasis via RNF41-dependent ASB6 degradation. These findings provide novel insights and important clues for targeted therapeutic strategies of CRC.
Insights
Circular RNA FNDC3B (circFNDC3B) suppresses colorectal cancer (CRC) stemness and metastasis by targeting RNF41 to degrade ASB6. This discovery offers new therapeutic strategies for CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) is a leading cause of cancer death globally, characterized by aggressive tumor progression and poor patient outcomes.
- Circular RNA FNDC3B (circFNDC3B) has been identified as a potential tumor suppressor in CRC, but its underlying mechanisms remain unclear.
- Understanding the regulatory roles of circRNAs in cancer stemness and metastasis is crucial for developing effective treatments.
Purpose of the Study:
- To elucidate the molecular mechanism by which circFNDC3B influences colorectal cancer stemness and metastasis.
- To investigate the interaction between circFNDC3B, RNF41, and ASB6 in the context of CRC progression.
- To explore the potential of circFNDC3B as a therapeutic target for colorectal cancer.
Main Methods:
- Quantitative reverse transcription-PCR (qRT-PCR), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and Western blotting were used to assess gene and protein expression.
- Sphere formation assays, flow cytometry, wound healing assays, and Transwell assays were employed to evaluate cancer stemness and metastatic potential.
- Bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down assays, and co-immunoprecipitation (Co-IP) were utilized to determine molecular interactions.
- In vivo liver metastasis models were established to assess the therapeutic efficacy of circFNDC3B and RNF41.
Main Results:
- Downregulation of circFNDC3B correlated with unfavorable survival in CRC patients and its overexpression suppressed CRC stemness and metastasis.
- circFNDC3B enhances RNF41 mRNA stability and expression by binding to FXR2, subsequently promoting ASB6 degradation via RNF41-mediated ubiquitination.
- Silencing RNF41 or overexpressing ASB6 counteracted the suppressive effects of circFNDC3B on CRC stemness and metastasis.
- Elevated ASB6 levels were associated with poor survival, and in vivo studies confirmed that circFNDC3B or RNF41 overexpression repressed tumor growth and metastasis by modulating ASB6.
Conclusions:
- N6-methyladenosine (m6A)-modified circFNDC3B inhibits colorectal cancer stemness and metastasis through RNF41-dependent ASB6 degradation.
- These findings reveal a novel regulatory pathway involving circFNDC3B, RNF41, and ASB6 in CRC progression.
- circFNDC3B represents a promising therapeutic target for mitigating colorectal cancer stemness and metastasis.
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