Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions and Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation and tumor growth Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting..

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Cholangiocarcinoma (CCA) is a highly lethal malignancy of the biliary tract with very few treatment options. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER2) have been considered as potential therapeutic targets in CCA. In the present study, we attempted to clarify the clinicopathological significance of all EGFR family members, EGFR, HER2, HER3 and HER4, across the full spectrum of CCAs. Immunohistochemistry and FISH were performed to validate expressions and genetic aberrations of these molecules retrospectively in 175 CCA patients. EGFR, HER3 and HER4 were overexpressed in 20 (30.8%), 8 (12.3%) and 41 (63.1%) of the 65 intrahepatic cholangiocarcinomas (IHCCs), and in 23 (20.9%), 13 (11.8%) and 62 (56.4%) of the 110 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, among which the rate was 4.5% (5/110). A significant association was identified between EGFR amplification and EGFR overexpression (P=0.002). Similarly, HER2 amplification was strongly associated with HER2 overexpression (P<0.001). Multivariate analysis suggested that EGFR overexpression is an independent prognostic factor in IHCC, but not in EHCC cases [HR (95% CI): 3.689 (1.253-10.587), P=0.018]. Notably, for the first time, we demonstrated HER4 expression is a prognostic factor in EGFR-negative IHCC patients. In vitro data further suggested a tumor-suppressor role of HER4 in CCA. siRNA knockdown of HER4 significantly increased RBE cell migration and invasion. By contrast, HER4 overexpression decreased proliferation of HuCCT-1 cells and their migratory and invasive capacity. In summary, our results revealed expression of the EGFR family members in CCA development and progression. CCAs differentially express HER2 protein based on tumor location. HER4 expression status allows stratification of CCA patients into different survival categories.

Our findings define a key role for ERG/SOX4 in the development of a subset of PCa and highlight the clinical importance of identifying molecularly defined tumor subgroups.