Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors.
The development of intratumoral hypoxia is a universal hallmark of rapidly growing solid tumors. Adaptation to the hypoxic environment, which is critical for tumor cell survival and growth, is mediated primarily through a hypoxia-inducible factor (HIF)-dependent transcriptional program. HIF activates genes that facilitate crucial adaptive mechanisms including increased glucose uptake and glycolysis and tumor angiogenesis, making it an important therapeutic target. However, the HIF-dependent transcriptional mechanism remains incompletely understood, and targeting HIF is a difficult endeavor. Here, we show that the orphan nuclear receptor estrogen-related receptors (ERRs) physically interact with HIF and stimulate HIF-induced transcription. Importantly, ERRs appear to be essential for HIF's function. Transcriptional activation of hypoxic genes in cells cultured under hypoxia is largely blocked by suppression of ERRs through expression of a dominant negative form of ERR or treatment with a pharmacological ERR inhibitor, diethylstilbestrol. Systematic administration of diethylstilbestrol severely diminished growth and angiogenesis of tumor xenografts in vivo. Because nuclear receptors are outstanding targets for drug discovery, the findings not only may offer mechanistic insights into HIF-mediated transcription but also may open new avenues for targeting the HIF pathway for cancer therapy.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, P.O. Box 103633, Gainesville, FL 32610, USA.
Ada
A
Ao
Heiman
H
Wang
Sushama
S
Kamarajugadda
Jianrong
J
Lu
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D000097983:ERRalpha Estrogen-Related Receptor
D004054:Diethylstilbestrol; D004968:Estrogens, Non-Steroidal; D051793:Hypoxia-Inducible Factor 1; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C490917:ESRRG protein, human; C107914:estrogen receptor-related receptor beta