Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2.
NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Md Morshedul
MM
Alam
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Keito
K
Okazaki
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Linh Thi Thao
LTT
Nguyen
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Nao
N
Ota
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Hiroshi
H
Kitamura
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575.
Shohei
S
Murakami
the Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, and.|CREST, AMED, Sendai, Miyagi 980-8575, Japan.
Hiroki
H
Shima
the Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, and.|CREST, AMED, Sendai, Miyagi 980-8575, Japan.
Kazuhiko
K
Igarashi
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, sekine@med.tohoku.ac.jp.
Hiroki
H
Sekine
From the Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, hozumim@med.tohoku.ac.jp.
Hozumi
H
Motohashi
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D006657:Histones; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone
Nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); electrophile; gene transcription; glucocorticoid receptor; histone acetylation; oxidative stress