Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

SIMPLE SUMMARY: Metastatic castration-resistant prostate cancer (mCRPC) is one of the leading causes of cancer-related death. mCRPC tumors feature high intratumoral cholesterol levels. Our current study shows that the nuclear receptor RORγ plays crucial roles in the aberrant cholesterol homeostasis of mCRPC. RORγ simultaneously stimulates cholesterol biosynthesis and suppresses cholesterol efflux programs through a RORγ and LXR crosstalk. Our study also demonstrated that RORγ antagonists alone or in combination with cholesterol-lowering drug statins are effective in inhibiting mCRPC cell and tumor growth. Our findings revealed a mechanism underlying the elevated cholesterol levels in mCRPC and suggested a potential therapeutic strategy for mCRPC patients. ABSTRACT: Metastatic castration-resistant prostate cancer (mCRPC) features high intratumoral cholesterol levels, due to aberrant regulation of cholesterol homeostasis. However, the underlying mechanisms are still poorly understood. The retinoid acid receptor-related orphan receptor gamma (RORγ), an attractive therapeutic target for cancer and autoimmune diseases, is strongly implicated in prostate cancer progression. We demonstrate in this study that in mCRPC cells and tumors, RORγ plays a crucial role in deregulation of cholesterol homeostasis. First, we found that RORγ activates the expression of key cholesterol biosynthesis proteins, including HMGCS1, HMGCR, and SQLE. Interestingly, we also found that RORγ inhibition induces cholesterol efflux gene program including ABCA1, ABCG1 and ApoA1. Our further studies revealed that liver X receptors (LXRα and LXRβ), the master regulators of cholesterol efflux pathway, mediate the function of RORγ in repression of cholesterol efflux. Finally, we demonstrated that RORγ antagonist in combination with statins has synergistic effect in killing mCRPC cells through blocking statin-induced feedback induction of cholesterol biosynthesis program and that the combination treatment also elicits stronger anti-tumor effects than either alone. Altogether, our work revealed that in mCRPC, RORγ contributes to aberrant cholesterol homeostasis by induction of cholesterol biosynthesis program and suppression of cholesterol efflux genes. Our findings support a therapeutic strategy of targeting RORγ alone or in combination with statin for effective treatment of mCRPC.