TY - JOUR
T1 - RORγ is a context-specific master regulator of cholesterol biosynthesis and an emerging therapeutic target in cancer and autoimmune diseases
AU - Zou, Hongye
AU - Yang, Nianxin
AU - Zhang, Xiong
AU - Chen, Hong Wu
N1 - Funding Information:
This work was supported in part by grants from the NIH (R01 CA206222 and R01CA224900), the Prostate Cancer Foundation (16CHAL02), and the US Department of Veterans Affairs, Office of Research & Development BL&D (I01 BX004271) to H-W. C.
Publisher Copyright:
© 2021 The Authors
PY - 2021
Y1 - 2021
N2 - Aberrant cholesterol metabolism and homeostasis in the form of elevated cholesterol biosynthesis and dysregulated efflux and metabolism is well recognized as a major feature of metabolic reprogramming in solid tumors. Recent studies have emphasized on major drivers and regulators such as Myc, mutant p53, SREBP2, LXRs and oncogenic signaling pathways that play crucial roles in tumor cholesterol metabolic reprogramming. Therapeutics such as statins targeting the mevalonate pathway were tried at the clinic without showing consistent benefits to cancer patients. Nuclear receptors are prominent regulators of mammalian metabolism. Their de-regulation often drives tumorigenesis. RORγ and its immune cell-specific isoform RORγt play important functions in control of mammalian metabolism, circadian rhythm and immune responses. Although RORγ, together with its closely related members RORα and RORβ were identified initially as orphan receptors, recent studies strongly support the conclusion that specific intermediates and metabolites of cholesterol pathways serve as endogenous ligands of RORγ. More recent studies also reveal a critical role of RORγ in tumorigenesis through major oncogenic pathways including acting a new master-like regulator of tumor cholesterol biosynthesis program. Importantly, an increasing number of RORγ orthosteric and allosteric ligands are being identified that display potent activities in blocking tumor growth and autoimmune disorders in preclinical models. This review summarizes the recent preclinical and clinical progress on RORγ with emphasis on its role in reprogramming tumor cholesterol metabolism and its regulation. It will also discuss RORγ functional mechanisms, context-specificity and its value as a therapeutic target for effective cancer treatment.
AB - Aberrant cholesterol metabolism and homeostasis in the form of elevated cholesterol biosynthesis and dysregulated efflux and metabolism is well recognized as a major feature of metabolic reprogramming in solid tumors. Recent studies have emphasized on major drivers and regulators such as Myc, mutant p53, SREBP2, LXRs and oncogenic signaling pathways that play crucial roles in tumor cholesterol metabolic reprogramming. Therapeutics such as statins targeting the mevalonate pathway were tried at the clinic without showing consistent benefits to cancer patients. Nuclear receptors are prominent regulators of mammalian metabolism. Their de-regulation often drives tumorigenesis. RORγ and its immune cell-specific isoform RORγt play important functions in control of mammalian metabolism, circadian rhythm and immune responses. Although RORγ, together with its closely related members RORα and RORβ were identified initially as orphan receptors, recent studies strongly support the conclusion that specific intermediates and metabolites of cholesterol pathways serve as endogenous ligands of RORγ. More recent studies also reveal a critical role of RORγ in tumorigenesis through major oncogenic pathways including acting a new master-like regulator of tumor cholesterol biosynthesis program. Importantly, an increasing number of RORγ orthosteric and allosteric ligands are being identified that display potent activities in blocking tumor growth and autoimmune disorders in preclinical models. This review summarizes the recent preclinical and clinical progress on RORγ with emphasis on its role in reprogramming tumor cholesterol metabolism and its regulation. It will also discuss RORγ functional mechanisms, context-specificity and its value as a therapeutic target for effective cancer treatment.
KW - Allosteric and orthosteric
KW - Antagonists and inverse agonists
KW - Breast
KW - Mevalonate pathway
KW - Oxysterols
KW - Pancreatic and prostate cancer
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U2 - 10.1016/j.bcp.2021.114725
DO - 10.1016/j.bcp.2021.114725
M3 - Review article
C2 - 34384758
AN - SCOPUS:85112824282
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
M1 - 114725
ER -