Abstract
Background: Liver X Receptors (LXRα, β) are oxysterol sensing nuclear receptors that regulate lipogenesis, cholesterol homeostasis and immune cell function. While oxysterols are agonist ligands of LXRs, sulfated oxysterols, catalytically produced by the SULT2B1b sulfotransferase, are LXR-inert. Increased SULT2B1b expression leads to attenuation of LXR signaling. In a previous report, we showed that SULT2B1b is undetectable in clinical samples of castration-resistant prostate cancer (CRPC), and its level is significantly reduced in a subset of primary prostate cancer. In cell models, genetic ablation of SULT2B1b exacerbated aggressive traits of CRPC, evident from EMT-like activation, enhanced invasion, faster xenograft tumor growth and reduced cell adhesiveness and stiffness in single-cell atomic force microscopy analysis. AKR1C3, which promotes androgen biosynthesis and shows elevated expression in advanced prostate cancer, is markedly upregulated in SULT2B-depleted cells. Elevated AKR1C3 leads to activation of the ERK1/2 Map kinase survival signal in CRPC cells. Results: We report here that AKR1C3 upregulation is a consequence of enhanced LXRα signaling in SULT2B1b-deficient cells, since the upregulation was abolished in multiple cell models when LXRα was silenced by siRNAs or inactivated by the small molecule inhibitor SR9243, which is an LXRs-selective inverse agonist. Conversely, LXR agonism induced by an oxysterol, or by the synthetic ligand GW3965, resulted in elevated AKR1C3 expression. Consistent with a recent report that the nuclear receptor ERRα is a positive regulator of AKR1C3, we found that ERRα ablation prevented AKR1C3 upregulation in SULT2B1b-deficient cells. Notably, LXRα inactivation caused marked reduction of ERRα, indicating that ERRα functions downstream of LXRα to induce AKR1C3 and ERK1/2. Dependence of ERRα and AKR1C3 expression on LXRα was observed in both androgen receptor (AR)-positive and AR-negative CRPC cells. Elevated ERRα in prostate cancer is known to be associated with a poor disease outcome. This association may be in part due to ERRα activation by cholesterol, which is the endogenous agonist ligand for ERRα (Cell Metab 23: 479, 2016), and high cholesterol is a risk factor for aggressive prostate cancer. Furthermore, statins, which inhibit cholesterol biosynthesis, are beneficial to CRPC patients with elevated blood cholesterol. We identified two cholesterol-responsive ERRα-binding sites in the far upstream region of the AKR1C3 promoter. This result confirms that ERRα plays a direct role in the transcriptional upregulation of AKR1C3. Significance: Our study establishes a novel LXRα→ERRα→AKR1C3→ERK1/2 survival axis that is activated in CRPC cells under SULT2B1b deficiency. The LXRα→ERRα regulatory axis may be exploited for developing novel therapeutics against AR-positive and AR-negative CRPC.
Prostate Cancer—Focus on Cholesterol
