PADI2-mediated citrullination promotes prostate cancer progression

Lin Wang, Guanhua Song, Xiang Zhang, Tingting Feng, Jihong Pan, Weiwen Chen, Muyi Yang, Xinnuo Bai, Yu Pang, Jindan Yu, Jinxiang Han*, Bo Han

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 PADI2 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 in vitro and in vivo. 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 in vitro and tumor growth in vivo. 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.

Original languageEnglish (US)
Pages (from-to)5755-5768
Number of pages14
JournalCancer Research
Volume77
Issue number21
DOIs
Publication statusPublished - Nov 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, L., Song, G., Zhang, X., Feng, T., Pan, J., Chen, W., ... Han, B. (2017). PADI2-mediated citrullination promotes prostate cancer progression. Cancer Research, 77(21), 5755-5768. https://doi.org/10.1158/0008-5472.CAN-17-0150