SIRT6 knockdown alleviates keratinocyte hyperproliferation and inflammation in psoriasis via modulating acetylation of FOXO1

The Sirtuins family (SIRT) has been implicated in numerous diseases, including psoriasis.However, the precise role of SIRT6 in psoriasis remains unclear. The analysis of publicly available RNA-seq data from GEO profiles showed that SIRT6 expression levels was significantly elevated in the lesional skins from patients with psoriasis, as compared to the non-lesional skins or the skins from normal healthy donors. It was also confirmed that SIRT6 and Ki67 expression was consistently upregulated inpsoriatic lesional skin,mouse models of psoriasis established by imiquimod treatment, and HaCat cells treated with M5. When SIRT6 was knocked down or inhibited in M5-treated HaCat cells, there was a significant suppression ofM5-induced increases in inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The upregulation of Ki67 expression and cell proliferation induced by M5 were also reduced. SIRT6 Inhibitor also significantly reduced the epidermal thickness and Ki67 expression levels in mouse models of psoriasis. Mechanistically, SIRT6 knockdown or inhibition enhanced the nuclear translocation of forkhead box O 1 (FOXO1) by increasing its acetylation level. M5 treatment reduced the nuclear FOXO1 levels via enhancing the nuclear efflux of Foxo1. Knockdown or inhibition of SIRT6 resulted in an increase in nuclear FOXO1 levels, not through enhancing its nuclear influx, but possibly by impeding the nuclear efflux of Foxo1. In conclusion, the knockdown of the SIRT6 promoted the nuclear translocation of FOXO1 by upregulating its acetylation level, thereby inhibiting M5-induced hyperproliferation and inflammation of keratinocyte. Given the crucial role of SIRT6 in psoriasis, it may represent a promising target for the development of small-molecule inhibitors with therapeutic potential for psoriasis.

Acetylation; FOXO1; Hyperproliferation; Keratinocyte; Psoriasis; SIRT6.