Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer

TL;DR

This study explores how a gene called SLC7A11, regulated by FOXA1 and a super-enhancer, contributes to prostate cancer progression and a new type of cell death called disulfidptosis.

Contribution

The study identifies a novel regulatory axis involving a super-enhancer, FOXA1, and SLC7A11 in disulfidptosis and prostate cancer progression.

Findings

SLC7A11 promotes cancer cell proliferation, migration, and invasion, and its overexpression triggers disulfidptosis under glucose starvation.

FOXA1 regulates SLC7A11 via a super-enhancer on chr14:37583488–37589585, and deleting this enhancer reduces disulfidptosis.

Pharmacological inhibition of glucose uptake with BAY-876 can induce disulfidptosis in prostate cancer cells.

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.

Figures