RAD21 promotes oncogenesis and lethal progression of prostate cancer

• 成果类型: Article
• 署名作者: Su, Xiaofeng A.; Stopsack, Konrad H.; Schmidt, Daniel R.; Ma, Duanduan; Li, Zhe; Scheet, Paul A.; Penney, Kathryn L.; Lotan, Tamara L.; Abida, Wassim; DeArment, Elise G.; Lu, Kate; Janas, Thomas; Hu, Sofia; Vander Heiden, Matthew G.; Loda, Massimo; Boselli, Monica; Amon, Angelika; Mucci, Lorelei A.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Uniformed Services University of the Health Sciences - USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; University of Texas System; UTMD Anderson Cancer Center; Johns Hopkins University; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Howard Hughes Medical Institute; American Cancer Society
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9292
• DOI: 10.1073/pnas.2405543121
• 发表日期: 2024-09-03
• 关键词: cell-cycle; expression; cohesin; aneuploidy; genes; assay; erg; transcription; association; Mutation

摘要

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long- term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21, with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.