Valproic acid downregulates heme oxygenase-1 independently of Nrf2 by increasing ubiquitination and proteasomal degradation
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28189672
DOI
10.1016/j.bbrc.2017.02.041
PII: S0006-291X(17)30309-1
Knihovny.cz E-resources
- Keywords
- Heme Oxygenase-1, Nrf2, Rhabdomyosarcoma, Ubiquitination, Valproic acid,
- MeSH
- Anticonvulsants pharmacology MeSH
- Cell Line MeSH
- Down-Regulation drug effects MeSH
- NF-E2-Related Factor 2 genetics metabolism MeSH
- Heme Oxygenase-1 genetics metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Valproic Acid pharmacology MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Proteasome Endopeptidase Complex metabolism MeSH
- Proteolysis drug effects MeSH
- Ubiquitination drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anticonvulsants MeSH
- NF-E2-Related Factor 2 MeSH
- Heme Oxygenase-1 MeSH
- Enzyme Inhibitors MeSH
- Valproic Acid MeSH
- Nfe2l2 protein, mouse MeSH Browser
- Proteasome Endopeptidase Complex MeSH
AIMS: Heme oxygenase-1 (HO-1; HMOX1 in human, Hmox1 in mice) is an antioxidative enzyme affecting wide range of sub-cellular processes. It was shown to modulate tumor growth or vascular-related diseases, thus being putative molecular target for tailored therapies. Therefore it is of importance to elucidate novel compounds regulating HO-1 activity/expression and to delineate mechanisms of their action. In the present study we aimed to understand mode of action of valproic acid (VA), an antiepileptic drug, on HO-1 expression. RESULTS: We demonstrated that HO-1 expression is decreased by VA at protein but not mRNA level in human alveolar rhabdomyosarcoma cell line CW9019. Nrf2 transcription factor, the activator of HO-1 expression through ARE sequence, was excluded as a mediator of HO-1 decrease, as VA downregulated Bach1, a Nrf2 repressor, concomitantly upregulating ARE activation. Also miRNA-dependent inhibition was excluded as a mechanism of HMOX1 regulation. However, co-immunoprecipitation assay showed a higher level of ubiquitinated HO-1 after VA treatment. Accordingly, MG132, an inhibitor of proteasomal degradation, reversed the effect of VA on HO-1 suggesting that decrease in HO-1 expression by VA is through protein stability. The inhibitory effect of VA on HO-1 was also observed in murine cells including embryonic fibroblasts isolated from Nrf2-deficient mice, what confirms Nrf2-independent effect of the compound. Importantly, VA decreased also HO-1 expression and activity in murine skeletal muscles in vivo. CONCLUSION: Our data indicate that VA downregulates HO-1 by acting through ubiquitin-proteasomal pathway leading to decrease in protein level.
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