Although localized prostate cancer is relatively indolent, advanced prostate cancer manifests with aggressive and often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we leveraged Sleeping Beauty (SB) transposon mutagenesis in a mouse model based on prostate-specific loss-of-function of Pten and Tp53 . Compared with control mice, SB mice developed more aggressive prostate tumors, with increased incidence of metastasis. Notably, a significant percentage of the SB prostate tumors display NEPC phenotypes, and the transcriptomic features of these SB mouse tumors recapitulated those of human NEPC. We identified common SB transposon insertion sites (CIS) and prioritized associated CIS-genes differentially expressed in NEPC versus non-NEPC SB tumors. Integrated analysis of CIS-genes encoding for proteins representing upstream, post-translational modulators of master regulators controlling the transcriptional state of SB -mouse and human NEPC tumors identified sirtuin 1 ( Sirt1 ) as a candidate mechanistic determinant of NEPC. Gain-of-function studies in human prostate cancer cell lines confirmed that SIRT1 promotes NEPC, while its loss-of-function or pharmacological inhibition abrogates NEPC. This integrative analysis is generalizable and can be used to identify novel cancer drivers for other malignancies.
Summary: Using an unbiased forward mutagenesis screen in an autochthonous mouse model, we have investigated mechanistic determinants of aggressive prostate cancer. SIRT1 emerged as a key regulator of neuroendocrine prostate cancer differentiation and a potential target for therapeutic intervention.