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.

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Despite lower antioxidant capacity as compared with normal cells, PCa cells adaptively synthesize more antioxidants like HO-1, Nrf2, and GPXs to cope with the continued ROS production. A wealth of studies have suggested that under the dynamic nonequilibrium of ROS, elevated antioxidant genes facilitate the maintenance of protumorigenic signaling and protect against oxidative-dependent death within tumor cells [ 56 ]. There is a 45% failure of PCa patients after high-dose radiotherapy against localized diseases, which may be partially due to elevated basic Nrf2 gene expression essential to resist hazardous environmental insults [ 57 ].…”

“…There is a 45% failure of PCa patients after high-dose radiotherapy against localized diseases, which may be partially due to elevated basic Nrf2 gene expression essential to resist hazardous environmental insults [ 57 ]. Overexpression of antioxidant gene KLF4 restores the redox balance of PCa cells and reduces ROS-dependent cell death induced by chemotherapy drugs, such as high concentrations of H2O2 and paraquat [ 56 , 58 ]. The silence of the KMTD2 gene could weaken the combination of antioxidant genes with FOXO3 DNA to downregulate the expressions of antioxidants, thereby enhancing the chemosensitivity of PCa cells [ 59 ].…”

Transcription Factor KLF14 and Metabolic Syndrome

“…The link between KLF proteins and regulation of cell cycle processes such as proliferation, differentiation, as well as cell adhesion and migration (15), and maintenance of pluripotency of stem cells (16) have been well established. More recently, several studies showed that KLFs also play important roles in cancer (14,109) [reviewed in (15)]. Stacey et al reported a new genomic locus associated with increased susceptibility to basal cell carcinoma (BCC) (110).…”

The role of KLF14 in multiple disease processes

“…However, the newest report of Luo XH suggested that KLF14 might have complete opposite function in different types of tumors. They found that KLF14 potentiate oxidative adaptation in castrate‐resistant prostate cancer via modulating heme oxygenase‐1 signaling and subsequently induce tumor growth …”

“…They found that KLF14 potentiate oxidative adaptation in castrate-resistant prostate cancer via modulating heme oxygenase-1 signaling and subsequently induce tumor growth. 45…”