N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

Abstract

SUMMARY MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.

A Prominent Couple

“…Importantly, FZD4 was upregulated upon T/E overexpression, and inhibition of FZD4 led to reduced phosphorylation of p38. These results confirmed reports that loss of cell adhesion and EMT are associated with FZD4-induced activation of WNT signaling [49].…”

“…Histone modifications play an important role in chromatin organization and transcriptional modulation indicating a link between histone modification and differential DNA methylation, which is supported in many recent studies [49,50]. This further suggested that dysregulation of histone modifying genes could lead to an altered DNA methylation in T/E expressing cells.…”

“…SiRNAmediated ERG knockdown in VCaP (Figure 4.5A) and NCI-H660 (Figure 4.5B) cells led to reduced expression of INSM1 and was accompanied by reduced mRNA levels of the neuroblastoma Myc oncogene (MYCN), which has previously been characterized as a driver of NEPC [48,49]. In contrast, REST expression in VCaP cells was increased after siRNA knockdown of ERG (Figure 4.5A).…”

“…The high upregulation of ALK1 in T/E expressing cells in our study was accompanied by augmented levels of TGF-β1 and TGF-β2 mRNA and protein, suggesting that autocrine TGF-β signaling mediates ALK1 pathway activation and phenotypic cellular changes in T/E cells [47,48]. The second route of T/E-induced signaling pointed towards FZD4 receptor-mediated WNT/β-catenin signaling as an important element [49,50]. Evidence for the role of WNT signaling was seen in the upregulation of transcription factors of the T cell factor/lymphoid enhancer family (TCF7L2, LEF1), increased β-catenin reporter activity and downregulation of the negative regulator CDH1 [51].…”

“…Increasing PSA level is a significant predictor of survival in patients who have newly diagnosed, metastatic PCa treated with continuous ADT [48]. CRPC can initially be treated by blocking AR signaling activity with the second-generation AR antagonist enzalutamide, and androgen synthesis inhibitors such as abiraterone [49,50]. The development of CRPC is driven by the genomic instability of PCa cells and multiple me-chanisms lead to the aberrant reactivation of AR signaling, including receptor promiscuity allowing alternative ligand binding, AR gene amplification [51,52], recruitment of alternating transcriptional coregulators [53][54][55][56] and AR splice variants.…”