Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition.
BACKGROUND
Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1-induced EMT.


OBJECTIVE
We sought to determine the role of SIRT1 in patients with nasal polyposis.


METHODS
The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxic markers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs.


RESULTS
SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not.


CONCLUSIONS
SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1-induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs.
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
Mingyu
M
Lee
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, Korea.
Dae Woo
DW
Kim
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
Haejin
H
Yoon
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
Daeho
D
So
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
Roza
R
Khalmuratova
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.
Chae-Seo
CS
Rhee
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Jong-Wan
JW
Park
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea. Electronic address: charlie@snu.ac.kr.
Hyun-Woo
HW
Shin
D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009297:Nasal Mucosa / Q000166:cytology; D009298:Nasal Polyps / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D010957:Plasmids; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D007073:Immunoglobulin E; D010047:Ovalbumin; D004247:DNA; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Nasal polyposis; animal model; epithelial-to-mesenchymal transition; hypoxia-inducible factor 1; sirtuin 1