Integrated Omics and Multicohort Analyses Identify an Enhancer Variant Linking Ferroptosis to Precision Therapy in Prostate Cancer
Year: 2025
Type: article
Study design: Observational Study
Abstract: Prostate cancer is the most prevalent cancer among men worldwide and exhibits significant genetic heritability. In this study, we performed an integrative analysis combining chromatin accessibility profiling, transcriptomics, and two-stage case-control studies, alongside an unbiased phenome-wide exploration in the FinnGen cohort. This comprehensive approach identified the enhancer-associated SNP rs7077830 at chromosome 10q11 as a critical modulator of prostate cancer susceptibility. Mechanistic investigations revealed that rs7077830 exerted allele-specific enhancer activity, driving NCOA4 expression via a ZNF384-mediated enhancer-promoter interaction. CRISPR/Cas9-mediated single-nucleotide editing confirmed the direct regulatory role of rs7077830 on NCOA4 and its contribution to prostate cancer progression. Functional studies demonstrated that NCOA4 acted as a tumor suppressor by promoting ferroptosis. Furthermore, NCOA4 expression modulated sensitivity to ferroptosis-inducing agents. Strikingly, rs7077830 genotypes were directly linked to ferroptosis status in prostate cancer. These findings highlight the role of noncoding genetic variants in prostate cancer pathogenesis, provide insights into enhancer-driven ferroptosis regulation, and suggest a promising therapeutic avenue for patients with prostate cancer carrying specific rs7077830 genotypes. SIGNIFICANCE: An enhancer mechanism mediated by a noncoding variant drives prostate cancer risk by regulating tumor suppressor expression and ferroptosis while conferring susceptibility to the potential of genotype-based precision therapeutic approaches.
Source: Cancer Research
Authors: Sheng Ma, Yue Ge, Zequn Lu, Junbiao Zhang, Qin Zhang, Yuzheng Peng, Zirui Xi, Hao Peng, Meng-Yao Xu, Zezhong Xiong, Yuan Gao, Yanan Wang, Le Li, Chunyu Zhang, Zheng Chao, Tengfei Li, Ruiyun Zhang, Qiang Zhang, David A. Horne, Baojun Wang, Xu Gao, Xu Zhang, Jianbo Tian, Jing Li, Meng Jin, Gong-Hong Wei, Zhihua Wang
Institutions: Tongji Hospital, Huazhong University of Science and Technology, Wuhan University, Northwestern University, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou Institute of Systems Medicine, University of Oulu, Xiangya Hospital Central South University, Xiamen University, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Chinese PLA General Hospital, Second Military Medical University, Changhai Hospital, Shanghai Medical College of Fudan University, Fudan University, Fudan University Shanghai Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4412936005