Researchers at Columbia University Irving Medical Center have identified a gene that drives the development of neuroendocrine prostate cancer (NEPC), an aggressive form of the disease. Their study showed that genetic or pharmacological inhibition of Sirtuin 1 prevents the growth of NEPC tumors in mice, laying the groundwork for future clinical studies aimed at developing new treatments for NEPC in humans.
Research lead Cory Abate-Shen, PhD, a professor at Columbia University Vagelos College of Physicians and Surgeons, is co-senior author of the researchers’ published paper in Journal of Experimental Medicine, titled “A forward genetic screen identifies Sirtuin 1 as a driver of neuroendocrine prostate cancer,” in which the team noted, “We demonstrate that expression of Sirt1 promotes NEPC while its silencing or pharmacological inhibition suppresses the NEPC phenotype.”
Prostate cancer is the most common cancer in men, and one in every six men will be affected by prostate cancer in their lifetime, the authors explained. Prostate cancer treatments have been focused on approaches to dampening androgen receptor (AR) signalling, and for men with recurrent or advanced prostate cancer the current standard of care is androgen deprivation therapy (ADT). However, it is well documented that ADT will eventually fail, leading to tumor recurrence and development of the ADT-insensitive aggressive prostate cancer variant, NEPC. “… while ADT initially leads to tumor regression, eventually tumors recur as castration-resistant prostate cancer (CRPC), so called because of its continued reliance on AR even in the absence of androgens,” the team continued.
Positively stained NEPC markers (top) are lost when Sirt1 is silenced (bottom). [© 2026 Nunes de Almeida et al. Originally published in Journal of Experimental Medicine.]The process through which ADT-responsive tumors transition towards NEPC tumors—a phenomenon known as lineage plasticity—remains unknown. “Elucidating the mechanisms governing this process may improve treatment by overcoming plasticity-associated drug resistance,” Abate-Shen added.
For their newly reported study the research team performed a Sleeping Beauty (SB) forwards genetic mutagenesis screen in mice looking for mutations that recurred across multiple independent prostate cancer tumors. They identified 75 candidate NEPC-promoting genes, the most promising of which was Sirtuin 1 (Sirt1). Sirt1 encodes an enzyme with a broad range of functions, including control of gene expression and metabolism.
The group first looked to a human prostate cancer cell line to characterize the role of Sirt1. In these cells, the induction of NEPC produced an increase in the expression of genes predicted to be activated by SIRT1 and a corresponding decrease in those predicted to be downregulated by this protein. Confirming these results, the group found that activation of Sirt1 in cells with low SIRT1 expression levels led to a robust increase in key NEPC markers.
Recapitulating their cell line data, the team found that silencing of Sirt1 profoundly reduced tumor growth in mice with NEPC, indicating that Sirt1 is indeed a promising target for NEPC treatment. They also treated the tumors with the FDA-approved SIRT1-inhibitor, Selisistat, which was originally developed for treatment of Huntington’s disease. Encouragingly, the researchers saw that Selisistat administration significantly reversed the NEPC phenotype. “Functional studies in human prostate cancer cell models and mouse organoid models using gain- and loss-of- function approaches in vitro and in vivo, as well as pharmacological inhibition, demonstrated that one of the top-ranked candidates, Sirt1, promotes NEPC,” they wrote in summary.
Tumors surgically removed from Sirt1-silenced mice (bottom) are significantly smaller than tumors removed from mice with wild-type Sirt1 expression. [© 2026 Nunes de Almeida et al. Originally published in Journal of Experimental Medicine.]“Our findings demonstrate that SIRT1 plays a pivotal role in promoting NEPC, revealing a context-dependent function that extends beyond general tumor growth to the regulation of lineage plasticity and neuroendocrine differentiation,” says Abate-Shen, adding that “this highlights SIRT1 as an attractive and clinically actionable target for lethal prostate cancer that warrants further investigation in future clinical studies.”
In their paper the team concluded, “Overall, our study establishes a generalizable computational and experimental framework that integrates SB mutagenesis with phenotypic, genomic, and transcriptomic analyses to identify novel cancer drivers … Importantly, our data suggest that targeting SIRT1 may suppress or reverse progression toward NEPC.”
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