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Taraxasterol acetate targets RNF31 to inhibit RNF31/p53 axis-driven cell proliferation in colorectal cancer
Chao-Tao Tang1, Jing Yang1, Zi-De Liu1
1Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Abstract:
Colorectal cancer (CRC) is the third most common cancer worldwide. Several studies have suggested that taraxasterol acetate (TA) can inhibit the growth of tumor cells. However, to date, it remains unclear how TA inhibits cell growth and how RNF31 functions as an oncogene. We examined the expression of RNF31 in CRC tissue samples via immunohistochemistry and elucidated the function of RNF31 in CRC cells by constructing a cell model with RNF31 depletion. A cycloheximide (CHX)-chase analysis and immunofluorescence assays were conducted to demonstrate that TA can promote RNF31 degradation by activating autophagy. We used the PharmMapper website to predict targets of TA and identified RNF31. CHX-chase experiments showed that TA could facilitate RNF31 degradation, which was inhibited by the administration of chloroquine. Immunofluorescence assays showed that RNF31 protein was colocalized with LC3I/II and p62, suggesting that TA promoted RNF31 degradation by activating autophagy. We also found that CRC patients with RNF31 overexpression had poorer survival than those with low RNF31 expression. The results of the CHX-chase experiment showed that depletion of RNF31 alleviated p53 degradation, which was inhibited by MG132. A series of co-immunoprecipitation (Co-IP) assays revealed that RNF31 interacts with p53 and promotes p53 ubiquitination and degradation. A Co-IP assay performed with a truncated RNF31 plasmid showed that the PUB domain interacts with p53. Moreover, the PUB domain is the key structure in the induction of p53 ubiquitination. Our findings reveal a key role of RNF31 in CRC cell growth and indicate a mechanism through which TA inhibits cell growth.
Insights
Taraxasterol acetate (TA) inhibits colorectal cancer (CRC) by promoting RNF31 protein degradation via autophagy. This mechanism involves RNF31 interacting with and degrading p53, offering new therapeutic insights for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Colorectal cancer (CRC) is a leading global cancer, necessitating novel therapeutic strategies.
- Taraxasterol acetate (TA) shows potential in inhibiting tumor cell growth, but its mechanism remains unclear.
- RNF31 is implicated as an oncogene in CRC, yet its precise role and regulation are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which Taraxasterol acetate (TA) inhibits colorectal cancer (CRC) cell growth.
- To investigate the role of RNF31 as an oncogene in CRC and its regulation by TA.
- To identify the molecular interactions and pathways involved in TA-mediated CRC inhibition.
Main Methods:
- Immunohistochemistry to assess RNF31 expression in CRC tissues.
- Cellular models with RNF31 depletion to study its function.
- Cycloheximide (CHX)-chase assays and immunofluorescence to analyze protein degradation and autophagy.
- PharmMapper for target prediction and Co-immunoprecipitation (Co-IP) assays for protein interaction studies.
Main Results:
- TA promotes RNF31 degradation by activating autophagy, evidenced by LC3I/II and p62 colocalization.
- RNF31 overexpression correlates with poorer survival in CRC patients.
- RNF31 interacts with p53, promoting its ubiquitination and degradation via its PUB domain.
- Depletion of RNF31 alleviates p53 degradation, suggesting a protective role against cancer progression.
Conclusions:
- Taraxasterol acetate (TA) inhibits colorectal cancer (CRC) growth by inducing RNF31 degradation through autophagy.
- RNF31 acts as an oncogene by interacting with and promoting the degradation of the tumor suppressor p53.
- These findings reveal a novel therapeutic mechanism for TA in CRC and highlight RNF31 as a potential therapeutic target.
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