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Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.
- Source :
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Scientific reports [Sci Rep] 2016 Sep 16; Vol. 6, pp. 33274. Date of Electronic Publication: 2016 Sep 16. - Publication Year :
- 2016
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Abstract
- Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37. Here we investigate a mechanism for the induction and also find that Entinostat up-regulates human β-defensin 1. Analysis of the CAMP promoter sequence revealed binding sites for the transcription factors STAT3 and HIF-1α. By using short hairpin RNA and selective inhibitors, we found that both transcription factors are involved in Entinostat-induced expression of LL-37. However, only HIF-1α was found to be recruited to the CAMP promoter, suggesting that Entinostat activates STAT3, which promotes transcription of CAMP by increasing the expression of HIF-1α. Finally, we provide in vivo relevance to our findings by showing that Entinostat-elicited LL-37 expression was impaired in macrophages from a patient with a STAT3-mutation. Combined, our findings support a role for STAT3 and HIF-1α in the regulation of LL-37 expression.<br />Competing Interests: R.S., G.H.G., B.A. are co-founders of Akthelia, a company that holds a patent for the use of Entinostat in the treatment of infections; (Strömberg R., Ottoson H., Agerberth B., Gudmundsson G., Miraglia E. & Nylen F. Antimicrobial compounds. Application: WO patent 2014-IB65678 2015063694, 2015).
- Subjects :
- Antimicrobial Cationic Peptides
Cathelicidins agonists
Cathelicidins metabolism
Genes, Reporter
HEK293 Cells
HT29 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit agonists
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Job Syndrome immunology
Job Syndrome pathology
Leukocytes, Mononuclear cytology
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear immunology
Luciferases genetics
Luciferases metabolism
Macrophages drug effects
Macrophages immunology
Macrophages pathology
Primary Cell Culture
Promoter Regions, Genetic
Protein Binding
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
STAT3 Transcription Factor agonists
STAT3 Transcription Factor antagonists & inhibitors
STAT3 Transcription Factor metabolism
Signal Transduction
Transcriptional Activation
Benzamides pharmacology
Cathelicidins genetics
Histone Deacetylase Inhibitors pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Job Syndrome genetics
Pyridines pharmacology
STAT3 Transcription Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 27633343
- Full Text :
- https://doi.org/10.1038/srep33274