Researchers at Columbia University Irving Medical Center have identified a gene that promotes the development of the aggressive disease neuroendocrine prostate cancer (NEPC). This study was published on May 28th. experimental medicine journal (gem), we show that genetic or pharmacological inhibition of sirtuin-1 prevents NEPC tumor growth in mice, laying the foundation for future clinical studies aimed at developing new treatments for NEPC in humans.
One in six men will develop prostate cancer during his lifetime. The current standard treatment is androgen deprivation therapy (ADT). However, it is well documented that ADT ultimately fails, leading to tumor recurrence and the development of the ADT-insensitive aggressive prostate cancer variant NEPC. The process by which ADT-responsive tumors transform into NEPC tumors, a phenomenon known as lineage plasticity, remains unclear.
“Unraveling the mechanisms that govern this process has the potential to overcome plasticity-related drug resistance and improve treatment,” says Cory Abbate Shen, a professor at Columbia University’s Vagelos College of Physicians and Surgeons, who co-lead the new study. gem Studied under Professor Andrea Califano, a colleague.
Abbate Shen’s team conducted a genetic screen in mice looking for mutations that recur in multiple independent prostate cancer tumors. They identified 75 candidate NEPC-promoting genes, the most promising of which was sirtuin 1 (Cert 1). Cert 1 It encodes enzymes with a wide range of functions, including regulating gene expression and metabolism.
The research group first focused on human prostate cancer cell lines and characterized their role. Cert 1. In these cells, induction of NEPC increased the expression of genes predicted to be activated by SIRT1 and correspondingly decreased the expression of genes predicted to be downregulated by this protein. Reviewing these results, the group Cert 1 Cells with low SIRT1 expression levels had a significant increase in key NEPC markers.
The research team resummarized the cell line data and found that Cert 1 The tumor growth in NEPC mice was significantly reduced. Cert 1 It is certainly a promising target for NEPC treatment. They also treated the tumor with selicistat, an FDA-approved SIRT1 inhibitor originally developed to treat Huntington’s disease. Interestingly, the researchers observed that administration of selicistat significantly reversed the NEPC phenotype.
Our findings demonstrate that SIRT1 plays a pivotal role in promoting NEPC and reveal context-dependent functions that extend beyond general tumor growth to the regulation of lineage plasticity and neuroendocrine differentiation, highlighting that SIRT1 is an attractive and clinically viable target in lethal prostate cancer, requiring further investigation in future clinical studies. ”
Cory Abate Shen, Professor, Columbia University Vagelos College of Physicians and Surgeons
sauce:
Rockefeller University Press
Reference magazines:
Nunez de Almeida, F. others. (2026). Forward genetic screen identifies Sirtuin1 as a neuroendocrine prostate cancer driver. Journal of Experimental Medicine. DOI: 10.1084/jem.20241484. https://rupress.org/jem/article/223/7/e20241484/282639/A-forward-genetic-screen-identifying-Sirtuin1-as-a
