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June 24, 2026Open Access

A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer

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Population

Mouse model with prostate-specific loss of Pten and Tp53, human prostate cancer cells, and mouse NEPC…

Comparison

Sleeping Beauty transposon mutagenesis; SIRT1… vs Control NPp53-SB(−) mice

Design

Preclinical

Key result

Sirtuin 1 (SIRT1) promotes aggressive neuroendocrine prostate cancer, and its pharmacological inhibition suppresses the disease in human prostate cancer cells and mouse organoids.

Authors

FAFrancisca Nunes de AlmeidaAVAlessandro VasciaveoAGArianna Giacobbe

Discussion

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Member takes

Overview

SIRT1 inhibition merits testing in NEPC models; animal data leave open human translation.

Key Points

  • This research aims to identify molecular drivers of aggressive neuroendocrine prostate cancer (NEPC).
  • Used Sleeping Beauty transposon mutagenesis in NPp53 mice with prostate-specific loss of Pten and Tp53.
  • Conducted gain- and loss-of-function studies in human prostate cancer cells and mouse NEPC organoids.
  • Analyzed recurrent common insertion sites and correlated them with gene expression.
  • NPp53-SB(+) mice developed more aggressive tumors with increased metastasis (specific rates not provided).
  • Sirtuin 1 (Sirt1) was prioritized as a key driver of NEPC through genomic and transcriptomic analysis.
  • Pharmacological inhibition of SIRT1 suppressed NEPC progression.

Structured PICO

P
Population
Mouse model with prostate-specific loss of Pten and Tp53 (NPp53 mice), human prostate cancer cells, and mouse NEPC organoids
I
Intervention
Sleeping Beauty (SB) transposon mutagenesis; SIRT1 gain- and loss-of-function; pharmacological inhibition of SIRT1
C
Comparator
Control NPp53-SB(−) mice
O
Outcome
Development of aggressive tumors, metastasis, and neuroendocrine prostate cancer (NEPC) phenotypes

SIRT1 is identified as a novel driver of neuroendocrine prostate cancer, suggesting it as a potential therapeutic target.

Cite This Study

Almeida et al. (2026) studied this question. Sirtuin 1 (SIRT1) promotes aggressive neuroendocrine prostate cancer, and its pharmacological inhibition suppresses the disease in human prostate cancer cells and mouse organoids.

synapsesocial.com/papers/6a3c238ad15afadd906fa4echttps://doi.org/10.1084/jem.20241484
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