SIRT1 attenuates nasal polypogenesis by suppressing HIF-1-mediated epithelial-to-mesenchymal transition

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

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

Results: SIRT1 transgenic (TG) mice had significantly fewer mucosal lesions with epithelial disruption and fewer nasal polyps 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 TG mice. In CRS sinonasal specimens, SIRT1 was downregulated in the mucosa from patients with polyps as compared with patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells (hNECs). The intranasal transfection of a sh-SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 TG mice. Finally, mucosal extracts from CRS without nasal polyps increased SIRT1 expression in nasal epithelial cells, and those from CRS with nasal polyps did not. 

Conclusion: SIRT1 suppressed nasal polyp formation, possibly due to inhibition of HIF-1-induced EMT. Thus, nasal epithelium SIRT1 may be a therapeutic target for nasal polyps.