Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer
Zhen Kang1,2, Bin Lin1,2, Zhi-Bin Ke1,2
1Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Abstract:
Prostate cancer (PCa) remains a major therapeutic challenge due to aberrant androgen receptor signaling and a remodeled tumor microenvironment. Disulfidptosis, a recently identified form of cell death characterized by cytoskeletal collapse under conditions of glucose deprivation and elevated SLC7A11 expression, presents a potential novel avenue for intervention. In this study, we integrated TCGA and GEO data and employed machine learning techniques to identify disulfidptosis-related genes in prostate cancer. Functional analyses using SLC7A11-overexpressing and knockout cell lines demonstrated that SLC7A11 promotes cellular proliferation, migration, and invasion, while its overexpression under glucose-starved conditions triggers disulfidptosis, also inducible pharmacologically using the glucose uptake inhibitor BAY-876. Through CUT&Tag, ChIP-seq, and luciferase assays, we identified FOXA1 as a key transcriptional regulator of SLC7A11, driven by a super-enhancer located at chr14:37583488-37589585. CRISPR-Cas9 deletion of this super-enhancer reduced FOXA1 and SLC7A11 expression, thereby protecting cells from disulfidptosis. These findings highlight the critical role of the SE/FOXA1/SLC7A11 regulatory axis in driving both disulfidptosis and tumor progression, suggesting that targeting this pathway, particularly in glucose-deprived tumor environments, may offer promising therapeutic strategies for PCa.
Insights
Researchers identified a new cell death pathway, disulfidptosis, linked to prostate cancer (PCa) progression. Targeting the SE/FOXA1/SLC7A11 pathway may offer novel therapeutic strategies for PCa, especially in low-glucose environments.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Prostate cancer (PCa) presents therapeutic challenges due to androgen receptor signaling and tumor microenvironment alterations.
- Disulfidptosis, a novel cell death form, involves cytoskeletal collapse under glucose deprivation and elevated SLC7A11, offering a potential therapeutic target.
Purpose of the Study:
- To identify disulfidptosis-related genes in prostate cancer using integrated data analysis.
- To elucidate the role of SLC7A11 and its regulatory mechanisms in PCa progression and disulfidptosis.
Main Methods:
- Integrated analysis of TCGA and GEO datasets with machine learning to identify key genes.
- Functional studies using SLC7A11-overexpressing and knockout cell lines.
- Molecular assays including CUT&Tag, ChIP-seq, luciferase assays, and CRISPR-Cas9 gene editing.
Main Results:
- SLC7A11 promotes PCa cell proliferation, migration, and invasion.
- SLC7A11 overexpression under glucose starvation induces disulfidptosis, which can be pharmacologically triggered by BAY-876.
- FOXA1 was identified as a key transcriptional regulator of SLC7A11, driven by a super-enhancer (SE) at chr14:37583488-37589585.
- Deletion of the SE significantly reduced FOXA1 and SLC7A11 expression, conferring resistance to disulfidptosis.
Conclusions:
- The SE/FOXA1/SLC7A11 regulatory axis is crucial for driving both disulfidptosis and tumor progression in PCa.
- Targeting this pathway, particularly in glucose-deprived tumor microenvironments, represents a promising therapeutic strategy for prostate cancer.
