KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the Transcription of PIK3R3

Abstract

The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 invitro and invivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-κB pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.