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Cancer Res. 2017 Nov 1;77(21):5755-5768. doi: 10.1158/0008-5472.CAN-17-0150. Epub 2017 Aug 17.

PADI2-Mediated Citrullination Promotes Prostate Cancer Progression.

Author information

1
Research Center for Medicinal Biotechnology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Shandong Academy of Medical Sciences, Jinan, China.
2
Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China.
3
Department of Urological Surgery, Shandong University Qilu Hospital, Jinan, China.
4
Department of Pathology, Shandong University Medical School, Jinan, China.
5
Department of Biochemistry, Shandong University Medical School, Jinan, China.
6
Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
7
Human Biology Department, University of Toronto, Toronto, Canada.
8
Department of Pathology, Taian City Central Hospital, Taian, China.
9
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
10
Research Center for Medicinal Biotechnology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Shandong Academy of Medical Sciences, Jinan, China. boh@sdu.edu.cn sams-h2016@163.com.
11
Department of Pathology, Shandong University Medical School, Jinan, China. boh@sdu.edu.cn sams-h2016@163.com.
12
Department of Pathology, Shandong University Qilu Hospital, Jinan, China.

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. Cancer Res; 77(21); 5755-68. ©2017 AACR.

PMID:
28819028
DOI:
10.1158/0008-5472.CAN-17-0150
[Indexed for MEDLINE]

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