N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Abstract

Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration resistant prostate cancers become androgen receptor (AR) signaling-independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome and interactome using in vivo, in vitro and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR-co-factors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage-specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

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Reference:

Berger A, Brady NJ, Bareja R, Robinson BD, Conteduca V, Augello MA, Puca L, Ahmed A, Dardenne E, Lu X, Hwang I, Bagadion AM, Sboner A, Elemento O, Paik J, Yu J, Barbieri CE, Dephoure N, Beltran H, Rickman DS. N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. J Clin Invest. 2019 Jul 1;130. pii: 127961. doi: 10.1172/JCI127961. PubMed PMID: 31260412.



Keywords: epigenetics, genetics, oncology, prostate cancer, N-Myc-mediated epigenetic reprogramming, lineage plasticity, advanced prostate cancer, EZH2 inhibition, neuroendocrine prostate cancer, androgen receptor.

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