Transcriptional activity of androgen receptor (AR) is governed by androgenic ligands and (thought to be) fine-tuned by post-translational modifications, such as SUMOylation. We have utilized genome-wide tools to study in an unbiased fashion the role of SUMOylation in the regulation of AR-directed gene programs in prostate cancer cells. Our results show that the SUMOylation does not simply repress the AR activity, but the modification modulates the receptor activity in a target gene/pathway and chromatin occupancy site selective manner. Fittingly, SUMO ligase PIAS1 functions as a target gene selective AR coregulator on prostate cancer cell chromatin, cooperating also with the pioneer factor FOXA1. Overall, the SUMOylation regulates gene programs relevant to prostate cancer growth. Androgen signaling also potentiallycrosstalks with other signaling pathways, including proinflammatory signaling. Based on our genome-wide analyses, androgen signaling can significantly modulate the TNFα-induced NF-κB cistrome by exposing latent RelA/p65-binding sites. Conversely, TNFα signaling is able to restrain the AR cistrome. Although the genomic crosstalk between the AR and the NF-κB may in part be accounted for a direct cooperation or competition of the two transcription factors at enhancers, the majority of the androgen and TNFα co-stimulation-specific chromatin binding events of the p65 are likely to result from indirect mechanisms. TNFα in fact affects chromatin binding of FOXA1 and PIAS proteins at p65-binding sites, suggesting their involvement in the crosstalk. Our transcriptome data indicate that the crosstalk between androgen and proinflammatory signaling can lead to activation of a distinct transcription program which may influence prostate carcinogenesis.
Biographical details: Jorma J. Palvimo, PhD, is professor of medical biochemistry at the University of Eastern Finland (UEF), Kuopio. Before becoming a faculty member of the UEF School of Medicine in 2004, JJP worked as an Academy of Finland junior and senior research fellow and university lecturer at the University of Helsinki, Finland. JJP become interested in androgen receptor and transcriptional regulation during his postdoctoral period in the Population Council and the Rockefeller University, NY. JJP is an author in 154 original research articles in international peer-reviewed journals. The publications concentrate on androgen receptor and signaling, transcription, SUMO modifications, nuclear receptor coactivators and corepressors, and chromatin.