title: ERRα augments HIF-1 signalling by directly interacting with HIF-1α in normoxic and hypoxic prostate cancer cells.
abstract: Adaptation of cancer cells to a hypoxic microenvironment is important for their facilitated malignant growth and advanced development. One major mechanism mediating the hypoxic response involves up-regulation of hypoxia-inducible factor 1 (HIF-1) expression, which controls reprogramming of energy metabolism and angiogenesis. Oestrogen-related receptor-α (ERRα) is a pivotal regulator of cellular energy metabolism and many biosynthetic pathways, and has also been proposed to be an important factor promoting the Warburg effect in advanced cancer. We and others have previously shown that ERRα expression is increased in prostate cancer and is also a prognostic marker. Here we show that ERRα is oncogenic in prostate cancer and also a key hypoxic growth regulator. ERRα-over-expressing prostate cancer cells were more resistant to hypoxia and showed enhanced HIF-1α protein expression and HIF-1 signalling. These effects could also be observed in ERRα-over-expressing cells grown under normoxia, suggesting that ERRα could function to pre-adapt cancer cells to meet hypoxia stress. Immunoprecipitation and FRET assays indicated that ERRα could physically interact with HIF-1α via its AF-2 domain. A ubiquitination assay showed that this ERRα-HIF-1α interaction could inhibit ubiquitination of HIF-1α and thus reduce its degradation. Such ERRα-HIF-1α interaction could be attenuated by XCT790, an ERRα-specific inverse agonist, resulting in reduced HIF-1α levels. In summary, we show that ERRα can promote the hypoxic growth adaptation of prostate cancer cells via a protective interaction with HIF-1α, suggesting ERRα as a potential therapeutic target for cancer treatment.
authors.affiliation: School of Biomedical Sciences, Chinese University of Hong Kong, People's Republic of China.
authors.forename: Chang
authors.initials: C
authors.lastname: Zou
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Xu
authors.forename: Dinglan
authors.initials: D
authors.lastname: Wu
authors.forename: Chi-Fai
authors.initials: CF
authors.lastname: Ng
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: David T
authors.initials: DT
authors.lastname: Yew
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vanacker
authors.forename: Franky L
authors.initials: FL
authors.lastname: Chan
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D031541:Fluorescence Resonance Energy Transfer; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D011960:Receptors, Estrogen; D057149:Ubiquitinated Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C497442:HIF1A protein, human
keywords: HIF-1α; hypoxia; oestrogen-related receptor-α; orphan nuclear receptor; prostate cancer