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

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Using an unbiased forward mutagenesis screen in an autochthonous mouse model, we have identified new mechanistic determinants of aggressive prostate cancer.emerged as a key regulator of neuroendocrine prostate cancer differentiation and a potential target for therapeutic intervention. teaser Although most prostate tumors are relatively indolent, advanced disease can progress to aggressive, often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we used() transposon mutagenesis in a mouse model having prostate-specific loss ofand(mice). Compared with controlmice, experimentalmice developed more aggressive tumors with increased metastasis. Notably,mice exhibited NEPC phenotypes with transcriptomic features that recapitulate human NEPC. Analysis of recurrent common insertion sites (CIS) and associated genes (CIS genes) identified genes differentially expressed between NEPC and non-NEPC tumors. Analysis of NEPC-enriched CIS genes by cross-species integration of genomic and transcriptomic data prioritized sirtuin 1 () as a candidate mechanistic determinant of NEPC. Gain- and loss-of-function studies in human prostate cancer cells and mouse NEPC organoids confirmed thatpromotes NEPC, while pharmacological inhibition suppresses it. Thus, integration of cross-species analyses with an unbiased forward genetic screen uncovered novel drivers of NEPC.