Abstract
Prostate cancer (PCa) is one of the leading causes of cancer related mortality and morbidity in the aging male population. The B-lymphoma and BAL-associated protein (BBAP) and Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), was originally identified as a binding partner of the B-aggressive lymphoma-1 protein and diphtheria-toxin-like ADP-ribosyltransferase-9 (BAL1/ARTD9). Here it is shown, that DTX3L and ARTD9 are both overexpressed in PCa cells. Together with ARTD8 (ADP-ribosyltransferase-8) they mediate proliferation, survival and chemo-resistance of PCa cells. The effects of DTX3L and ARTD9 are dependent on the signal transducer and activator of transcription factor 1 (STAT-1). STAT-1 is known as a tumor suppressor, activated by interferon γ (IFNγ). Its antitumor effects are mainly based on the activation of the transcription of the interferon responding factor 1 (IRF1). New reports showed that a constitutively activated STAT-1 leads to an IFNγ- and chemo-resistance of tumors and acts as an oncogene. Such a situation occurred also in the analyzed PCa cells. The presented study shows that DTX3L and ARTD9 repress the expression of IRF1. DTX3L also mediates migration of PCa cells in a STAT-1 and STAT-3-dependent manner. However, migration is not dependent on IFNy/IRF1. Together, this study suggests that the combined inhibition of STAT-1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate cancer
Bachmann, Samia Beatrice