Yang Nianxin, Yang Yatian, Huang Zenghong, Chen Hong-Wu
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
National Cancer Institute Designated Comprehensive Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
Cancers (Basel). 2022 Jun 24;14(13):3110. doi: 10.3390/cancers14133110.
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.
转移性去势抵抗性前列腺癌（mCRPC）的特征是肿瘤内胆固醇水平较高，这是由于胆固醇稳态的异常调节所致。然而，其潜在机制仍知之甚少。维甲酸受体相关孤儿受体γ（RORγ）是癌症和自身免疫性疾病颇具吸引力的治疗靶点，与前列腺癌进展密切相关。我们在本研究中证明，在mCRPC细胞和肿瘤中，RORγ在胆固醇稳态失调中起关键作用。首先，我们发现RORγ激活关键胆固醇生物合成蛋白的表达，包括HMGCS1、HMGCR和SQLE。有趣的是，我们还发现RORγ抑制可诱导胆固醇流出基因程序，包括ABCA1、ABCG1和ApoA1。我们的进一步研究表明，胆固醇流出途径的主要调节因子肝脏X受体（LXRα和LXRβ）介导RORγ在抑制胆固醇流出中的功能。最后，我们证明RORγ拮抗剂与他汀类药物联合使用在杀死mCRPC细胞方面具有协同作用，通过阻断他汀类药物诱导的胆固醇生物合成程序的反馈诱导，并且联合治疗比单独使用任何一种药物都能产生更强的抗肿瘤作用。总之，我们的研究表明，在mCRPC中，RORγ通过诱导胆固醇生物合成程序和抑制胆固醇流出基因导致异常的胆固醇稳态。我们的发现支持了一种单独靶向RORγ或与他汀类药物联合使用以有效治疗mCRPC的治疗策略。
