Targeting the MYCN–PARP–DNA Damage Response Pathway in Neuroendocrine Prostate Cancer

Abstract

Purpose: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC).Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN-PARP-DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivo.Conclusions: Our results identify a novel MYCN-PARP-DDR pathway that is driven by N-MYC in a subset of CRPCAdeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC.

Heterochromatin Protein 1α Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer

“…Another potential mechanism underlying the essential function of HP1a in NEPC aggressiveness is that HP1a depletion impaired DNA damage response (DDR) machineries, which is in accordance with previous studies (46,47). Most recently, another study also reported that a DDR pathway is enriched in NEPC, contributing to NEPC cell proliferation (48). Overall, HP1a could potentially serve as a therapeutic target for effective management of developed NEPC.…”

Phosphoribosyl pyrophosphate synthetases 2 knockdown inhibits prostate cancer progression by suppressing cell cycle and inducing cell apoptosis

“…It has become a truism that sustaining proliferation is an important hallmark of cancer [22]. c-MYC has been founded an elevated expression in PCa and multiple studies shown c-MYC can induce tumor cells proliferation and regulate cell cycle though MYC-responsive genes [7,[23][24][25]. Cell cycle genes expression level has been founded that associate with the timing of PCa metastasis, as an independent factor [26].…”

Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer

“…However, another study by Zang et al indicates that ELL2 has an important role in DNA damage response and repair. This enables ELL2 loss to function like a double edge sword which on one hand can induce prostate carcinogenesis, and on the other can sensitize cells to radiation therapy [41]. Human kallikrein-related peptidase 2 (KLK2, previously known as hK2) is a secreted serine protease from the same gene family as PSA.…”