IL-22 Increases Metastatic Properties in Androgen-Independent Prostate Cancer

Abstract

Abstract New evidence is emerging that suggests that a subpopulation of individuals characterized as metabolically abnormal obese (“MAO”; i.e.: co-morbid Type 2 diabetes (T2D), hypertension and systemic inflammation) have a much greater risk for cancer mortality compared to obese but metabolically healthy individuals (“MHO”; i.e.: non-diabetic, lack hypertension, non-inflamed). Because MAO individuals have systemic and local adipose inflammation associated with obesity co-morbidities, it is now hypothesized that alterations to signal transduction pathways in the tumor microenvironment (which come as a result of increased T2D-associated Th17 cytokines (IL-17A, IL-17F, IL-21, IL-22, etc.)), lead to a more advanced, pro-metastatic cancer phenotype. Furthermore, additional observations have also shown that Bromodomain and Extraterminal domain (BET) proteins (BRD2, BRD3 and BRD4) act as transcriptional effectors for these Th17 cytokines. Based on these data, we sought to determine whether (i); T2D-associated Th17 cytokines increase metastatic properties in androgen-independent prostate cancer cells, (ii) signaling pathways utilize Th17 cytokines to exacerbate metastatic properties and (iii) BET proteins act as effectors for Th17 cytokine signaling. Here we report that IL-22 increases migration and invasion in androgen-independent prostate cancer. This phenotype is achieved, in part, through the activation of STAT3 in a BRD4-dependent manner. Moreover, BRD2 opposes BRD4 in this process. Overall, these results identify a novel mechanism that is critical for prostate cancer metastasis.