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Loss of AR-regulated AFF3 contributes to prostate cancer progression and reduces ferroptosis sensitivity by
Aoyu Fan1, Yunpeng Li1, Yunyan Zhang1
1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200030, China.
Abstract:
Prostate cancer (PCa) is one of the most common cancers affecting the health of men worldwide. Castration-resistant prostate cancer (CRPC), the advanced and refractory phase of prostate cancer, has multiple mechanisms of resistance to androgen deprivation therapy (ADT) such as AR mutations, aberrant androgen synthase, and abnormal expression of AR-related genes. Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. However, many areas in this pathway are still worth exploring. In this study, single-cell sequencing analysis was utilized to scrutinize significant genes in the androgen receptor (AR) pathway related to CRPC. Our analysis of single-cell sequencing combined with bulk-cell sequencing revealed a substantial downregulation of AR-regulated AFF3 in CRPC. Overexpression of AFF3 restricted the proliferation and migration of prostate cancer cells whilst also increasing their sensitivity towards enzalutamide, while knockdown of AFF3 had the opposite effect. To elucidate the mechanism of tumor inhibition by AFF3, we applied GSVA and GSEA to investigate the metabolic pathways related to AFF3 and revealed that AFF3 had an impact on fatty acids metabolism and ferroptosis through the regulation of ACSL4 protein expression. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.
Insights
Researchers discovered that AFF3 is significantly downregulated in castration-resistant prostate cancer (CRPC). Restoring AFF3 levels may overcome drug resistance and improve treatment outcomes for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) is a prevalent malignancy in men globally.
- Castration-resistant prostate cancer (CRPC) is an advanced stage characterized by resistance to androgen deprivation therapy (ADT).
- Mechanisms of CRPC resistance include AR mutations, altered androgen synthesis, and dysregulated AR-related genes, necessitating further research into novel therapeutic targets.
Purpose of the Study:
- To investigate the role of androgen receptor (AR) pathway genes in CRPC using single-cell sequencing.
- To identify novel biomarkers and therapeutic strategies for overcoming drug resistance in CRPC.
Main Methods:
- Single-cell and bulk-cell sequencing analysis to identify key genes in the AR pathway.
- Functional assays (overexpression and knockdown) to assess the impact of AFF3 on prostate cancer cell behavior.
- Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA) to explore metabolic pathways.
- Correlation analysis and flow cytometry to investigate the relationship between AFF3, ACSL4, and ferroptosis.
Main Results:
- A significant downregulation of AR-regulated AFF3 was observed in CRPC.
- Overexpression of AFF3 inhibited prostate cancer cell proliferation and migration, enhancing sensitivity to enzalutamide.
- AFF3 influences fatty acid metabolism and ferroptosis by regulating ACSL4 protein expression.
- AFF3 impacts CRPC cell line sensitivity to ferroptosis inducers via ACSL4 regulation.
Conclusions:
- AFF3 downregulation is a key event in CRPC development and drug resistance.
- AFF3 plays a critical role in regulating metabolic pathways, including fatty acid metabolism and ferroptosis.
- AFF3 may serve as a novel prognostic biomarker and a potential therapeutic target for CRPC.
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