Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

Abstract

Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.

Fig. 1. Regulatory mechanism of RORα through canonical and noncanonical pathways in cancer.

Posttranslational modification by SUMOylation stimulates RORα to function as a direct TF on target gene promoters. Phosphorylation alters the direction of RORα functioning as a coregulator. Different signals can also change the roles of RORα-transregulating activities, leading to recruitment of p53-dependent target gene promoters as coactivators.

Fig. 2. Attenuation of inflammation by RORα.

Attenuated activation of NF-κB target genes by RORα contributes to survival and tumorigenesis prevention. Infectious agents lead to activation of NF-κB signaling, resulting in changes in the microenvironment to invoke immune responses and increase permeability in tissues, such as the intestine. Under ROR-mediated NF-κB target gene suppression, the functions of damaged cells are restored to reduce hyperinflammation. The anti-inflammatory roles of RORα further induce effective cytotoxic function in CD8+ T cells, resulting in cancer cell death. Activation of RORα with selective agonists, such as SR1078 and cholesterol sulfate, result in stimulatory effector responses of CD8+ T cells.

Fig. 3. Transcriptional regulation of cerebellum development and the circadian clock via RORα and REV-ERBs.

RORα controls Purkinje cell maturation through transcriptional activation of several target genes, such as Shh, Slc1a6, Itpr1, Pcp4, and Pcp1. Direct recruitment of RORα to target gene promoters positively regulates adequate expression for dendritic differentiation of Purkinje cells. Both RORα and REV-ERBs competitively control BMAL1 and CLOCK gene expression via RORE; RORα and REV-ERBs positively and negatively regulate BMAL1 and CLOCK, respectively. The BMAL1 and CLOCK generated cooperate at the E BOX to induce downstream target gene expression of PER and CRY, maintaining the master axis of the circadian rhythm.

Fig. 4. Regulation of RORα in lipid homeostasis.

Transcriptional regulation of lipid homeostasis mediated by PPAR is inhibited by RORα. Transcriptional activation of PPARγ with PGC-1α and transcriptional repression of RORα with HDAC3 balance each other at the promoters of PPAR-dependent target genes. Simultaneously, AMPK activation and antagonized LXRα expression by RORα results in reduced expression of lipogenic genes, such as SREBP-1 and FAS. Downregulated SREBP-1 results in decreased fatty acid oxidation and lipogenic effects.

Fig. 5. Target gene activation or repression by RORα and functions of RORα.

Circadian rhythm, lipid homeostasis, anticancer, and anti-inflammatory effects are integrated by processes in which RORα plays key roles. Direct activation of RORα via RORE may result in balanced circadian clock gene expression and different responses might be repressed by the same TF through binding of different PPREs. Evidence indicates that RORα functions in transrepression through other TFs such as β-catenin and NF-κB, which are master regulators of tumorigenesis and inflammation, respectively. The roles of RORα in health and disease are likely to depend on which cellular response is switched on and the context in which target selection occurs via RORα.