PADI2-Mediated Citrullination Promotes Prostate Cancer Progression

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 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..

Citrullination in Cancer

“…Although tumor-associated PAD2 was overexpressed in biopsies from patients with castration-resistant prostate cancer (CRPC; ref. 40), a downregulation of intertumoral PAD2 expression was identified in a cohort of patient with colorectal cancer specimens in comparison with normal mucosa of healthy control tissues (41).…”

“…In particular, PAD2-driven citrullination in the nucleus activated the androgen receptor pathway, whereas PAD2 stabilized the androgen receptor and promoted its translocation to the nucleus. Prostate cancer cells treated with PAD inhibitor Cl-amidine and PAD2-knockdown prostate cancer cells both exhibited a delay in cancer progression in vitro and in vivo (40). The authors, however, did not explore which proteins and residues were citrullinated, thus providing little mechanistic explanation for the observed findings.…”

“…Recent evidence suggested the involvement of citrullination in Androgen signaling in prostate cancer (40). PAD2 was upregulated in patients with CRPC and overexpression of PAD2 by prostate cancer cells induced a CRPC-like phenotype in mouse xenografts, which was mediated by androgen receptor signaling.…”

Possible role of Porphyromonas gingivalis in orodigestive cancers

“…The host has also intrinsic sources of citrullination through genes coding for a family of five calcium-dependent enzymes named peptidyl-arginine deiminases (PAD 1, 2, 3, 4/5 and 6), which are quite similar but not identical to PPAD. The host PADs have been linked to various human and animal cancers [94][95][96][97]. Thus, Kholia et al [96] reported that the expression level of PAD2 and PAD4 and the deimination of cytoskeletal actin were increased during stimulation of prostate cancer cells (PC3) with microvesiculate, which is involved in the progression of cancer.…”

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

“…Peptidylarginine-deiminase (PADI2), known to catalyze the posttranslational deamination of proteins, is associated with increased AR levels in CRPC by protecting it from UPD. 40 BMI1, a Polycomb group protein (PcG), stabilizes both AR and AR-V7 splice variant by physical interaction at the N-terminus of AR and thereby masking the MDM2 binding site required for degradation by proteasome. 41 This observation raises the possibility of other factors being necessary for AR chromatin occupancy, to modulate AR stability.…”