Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease

Orphan nuclear receptors, in a manner comparable to classic steroid hormone receptors, regulate key developmental and physiological processes. However, the lack of appropriate pharmacological tools has often hindered the identification and study of their biological functions. In this review, we demonstrate that functional and physiological genomics are effective alternatives to discover biological functions associated with orphan nuclear receptors. Indeed, we document that these approaches have allowed for the unambiguous identification of the estrogen-related receptors (ERRs) α, β, and γ (NR3B1, 2, and 3) as global regulators of cellular energy metabolism. We further show that although the three ERR isoforms control analogous gene networks, each isoform performs unique biological functions in a tissue-specific manner in response to a variety of physiological stressors. Finally, we discuss how the activity of the three ERR isoforms contributes to the development and progression of metabolic diseases as well as to the adaptation of cancer cells to their unique bioenergetic requirement. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.     

ERRs and cancers: effects on metabolism and on proliferation and migration capacities

ERRs are orphan members of the nuclear receptor superfamily which, at least for ERRα and ERRγ display important roles in the control of various metabolic processes. On other hand, correlations have been found between the expression of ERRα and γ and diverse parameters of tumor progression in human cancers. Whereas it is tempting to speculate that ERR receptors act in tumors through the regulation of metabolism, recent data have suggested that they also may directly regulate tumor proliferation and progression independently of their effects on metabolism. The two aspects of tumoral functions of ERR receptors are the purpose of the present review.     

ERRβ splice variants differentially regulate cell cycle progression

Orphan receptors comprise nearly half of all members of the nuclear receptor superfamily. Despite having broad structural similarities to the classical estrogen receptors, estrogen-related receptors (ERRs) have their own unique DNA response elements and functions. In this study, we focus on 2 ERRβ splice variants, short form ERRβ (ERRβsf) and ERRβ2, and identify their differing roles in cell cycle regulation. Using DY131 (a synthetic agonist of ERRβ), splice-variant selective shRNA, and exogenous ERRβsf and ERRβ2 cDNAs, we demonstrate the role of ERRβsf in mediating the G1 checkpoint through p21. We also show ERRβsf is required for DY131-induced cellular senescence. A key novel finding of this study is that ERRβ2 can mediate a G2/M arrest in response to DY131. In the absence of ERRβ2, the DY131-induced G2/M arrest is reversed, and this is accompanied by p21 induction and a G1 arrest. This study illustrates novel functions for ERRβ splice variants and provides evidence for splice variant interaction.