Interplay of Developmental Hippo-Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

Abstract

Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related 'hubs' such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR-Hippo-Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.

Keywords: DNA damage response (DDR); Hippo pathway; Notch pathway; interplay; prostate cancer.

Figure 1

Schematic representation of the DDR, Hippo and Notch signaling pathways in prostate cancer. (A). Mutations in DDR genes including ATM, TP53, BRCA1/2 and RAD51 are likely implicated in prostate carcinogenesis. The DDR pathway is largely conserved among different types of human cancer. (B). The Hippo kinase cascade is actively involved in prostate cancer. One of the routes through which YAP activity may be affected in prostate cancer is via MST1 kinase ubiquitination and subsequent proteosomal degradation, elicited by the molecular chaperone HSP27. Upon MST1 degradation, YAP translocates to the nucleus where it resumes its transcription coregulator activity. ETS factors and ETS-regulated genes, such as ERG, also have an important role in YAP and TAZ regulation. Especially ERG, apart from regulating the expression of YAP1, it can also bind to YAP1/TEAD binding sites and transactivate Hippo target genes. (C). The Notch pathway is deeply involved in prostate tumorigenesis. When a Notch ligand (Delta-like 1/3/4 or Jagged-1/2) binds to Notch transmembrane receptors (Notch 1/2/3/4), the receptors are cleaved by members of Metalloprotease (ADAM) family and γ-secretase. This cleavage releases the Notch intracellular domain (NICD), which translocates to the nucleus, where it regulates the expression of genes including MYC, HES, HEY, Cyclin D, etc.

Figure 2

DDR/Hippo/Notch pathway interplay in prostate cancer. Schematic representation of the DDR/Hippo/Notch pathway crosstalk in prostate cancer through the AR, ERG, AKT and TLK1 molecular hubs (1–4) boxed in yellow. Stimulatory effects between different pathway components are represented with blue lines while inhibitory signals are marked in red.