KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer

Abstract

Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.