2. Academic Validation
  3. Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer

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

  • Cell Death Dis. 2025 Dec 3. doi: 10.1038/s41419-025-08227-2.
Zhen Kang # 1 2,  Bin Lin # 1 2,  Zhi-Bin Ke # 1 2,  Qing-Shui Zheng 1 2,  Xue-Yi Xue 1 2 3,  Yong Wei 4 5,  Ning Xu 6 7 8
Affiliations

Affiliations

  • 1 Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 2 Department of Urology, National Region Medical Centre, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 3 Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 4 Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 5 Department of Urology, National Region Medical Centre, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 6 Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 7 Department of Urology, National Region Medical Centre, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • 8 Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China. [email protected].
  • # Contributed equally.
PMID: 41330917 DOI: 10.1038/s41419-025-08227-2
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.

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