Abstract B059: Identification of cohesin RAD21 as a novel aneuploidy-associated marker driving prostate cancer progression by mitigating toxic DNA damage

Abstract

Abstract Prostate cancer (PCa) is one of the most common cancers among men, leading to the second cause of death for men with cancers in the US. Aneuploidy, featured by imbalanced chromosome numbers, is a hallmark of cancer. Epidemiology studies on primary PCa cohorts of Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy correlate with lethal progression in PCa. However, the detail mechanisms of how aneuploidy drives aggressiveness of PCa are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequently gain events that occur in around 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained the odds ratio (OR) for each. Then, we ranked the ORs for lethal progression and identified several important genes highly associated with lethality when overexpressed. Among them, the cohesin subunit gene, RAD21, is one of the top associators. Increased RAD21 mRNA level, per se, is highly correlated with lethality in all PCa cases, and the lethality is synergistically aggravated in the cases with both increased RAD21 expression and chr 8q gains. indicating that RAD21 cooperates with other chr 8q genes to drive cancer progression and chr 8q gains. To determine how RAD21 overexpression promotes PCa, we studied the effect of overexpression of RAD21 in early prostatic oncogenic events. We utilized the isogenic mouse prostate organoid models carrying an inducible the fusion-oncogene, TMPRSS2-ERG (T-ERG), which 50% of PCa cases harbor. We found that induction of T-ERG leads to a strong oncogenic replication stress at an early stage. Such stress results in an increase in apoptosis and growth impairment in these primary organoids. Overexpression of RAD21, mimicking the chr 8q gain situation, mitigates such replication stress and rescues the growth defect caused by T-ERG. These data suggest the role of increased RAD21 in promoting oncogenic growth of PCa cells by reducing oncogenic toxicity at an early stage. In addition, we showed that such role of RAD21 overexpression sustains in the more advanced cancerous organoid (ERG positive and PTEN loss) and promotes the growth of the cancer organoids. Consistently, increased RAD21 expression correlates with increase proliferative markers in human prostate cancer cases. In conclusion, we identified that overexpression of multiple chr 8q genes are correlated with lethal progression in primary PCa, and RAD21 is one of such genes. Increased RAD21 plays a fundamental role in reducing toxic DNA damage caused by prostatic oncogenesis. Citation Format: Xiaofeng A Su, Konrad H Stopsack, Daniel R Schmidt, Duanduan Ma, Zhe Li, Thomas Janas, Matthew G Vander Heiden, Kathryn L Penny, Paul A Scheet, Tamara L Lotan, Angelika Amon, Lorelei A Mucci. Identification of cohesin RAD21 as a novel aneuploidy-associated marker driving prostate cancer progression by mitigating toxic DNA damage [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B059.