Citrullination of AKT2 catalyzed by PAD1 facilitates the maintenance of stemness characteristics of ovarian cancer stem-like cells in ovarian cancer

The presence of ovarian cancer stem-like cells (OCSLCs) is a crucial driving force for malignant progression, metastasis, and tumor recurrence. However, the mechanisms underlying the activation and maintenance of stemness in OCSLCs still remain elusive. Here, we report an increased expression of peptidylarginine deiminase 1 (PAD1) in ovarian cancer cells, particularly within the CD133+ subset or cisplatin-resistant ovarian cancer cells, which is positively associated with the upregulation of stemness-related markers and the maintenance of stemness in OCSLCs. To explore the mechanism through which PAD1 mediates such effects, we show that PAD1 specifically binds to the kinase domain of AKT2 and catalyzes citrullination of AKT2 at arginine 202. Moreover, PAD1 gene silencing, inhibiting AKT2 citrullination, or mutation of AKT2 equally decreases the tumor initiating ability of ovarian cancer cells both in vitro and in vivo. We propose that targeting PAD1/AKT2/CEBPb signaling axis in OCSLCs may be more effective in preventing ovarian cancer progression and overcoming chemoresistance in ovarian cancer therapy.