UC Davis

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.Treatment-induced neuroendocrine prostate cancer (tNEPC) is an advanced, aggressive, and treatment-resistant subtype of prostate cancer that has lost dependency on androgen receptor (AR) signaling and develops neuroendocrine traits. However, the mechanisms by which tNEPC cells survive and proliferate are still poorly understood. Histone deacetylases (HDACs) have been studied in various types of cancers, and a number of HDAC inhibitors has been developed and tested in clinical studies. In this study, we demonstrate that in tNEPC cells, HDACs play vital role in tNEPC cell survival and proliferation, while also possess potential anti-cancer functions. First, we found that HDAC inhibition blocks NEPC cell growth. Notably, HDAC pan-inhibitors and some specific HDAC-selective inhibitors display high potency in tNEPC cell growth inhibition. Next, we found that HDAC inhibitors downregulate cell cycle and cell survival related gene programs. Interestingly, some pro-metastasis and neuroendocrine development gene programs are induced by HDAC inhibitors. Finally, using specific HDAC-selective inhibitors, we identified several potential candidates that play essential roles in tNEPC cells, including HDAC1, HDAC3, HDAC4, and HDAC5. Together, our findings identify HDACs as potential therapeutic targets for tNEPC and point out that additional target-specific compounds with less non-intended side-effects need to be developed.