LncRNA UCA1 promotes keratinocyte-driven inflammation via suppressing METTL14 and activating the HIF-1α/NF-κB axis in psoriasis

Abstract

Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

Meta-analysis of RNA sequencing data from 534 skin samples shows substantial IL-17 effects in non-lesional psoriatic skin

“…25 Additionally, the upregulation of UCA1 (log 2 FC: 1.97), a keratinocyte-specific lncRNA, underscores its role in the interplay between psoriatic keratinocytes and immunity. 26 While PRINS has been previously implicated in psoriasis, 10 our study did not replicate this. Given their finely tuned regulatory capacities, lncRNAs exhibit great potential as biomarkers for diagnosis, disease development and treatment in psoriasis.…”

N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway

“…In hepatocellular carcinoma and colorectal cancer, METTL3 mediates the m6A modification of HIF-1α mRNA, and then extends its half-life and improves stability and translation, subsequently interacting with target genes related to glycolysis[ 34 , 35 ]. However, in cells with METTL14 knockdown used for a psoriasis study, the m6A level of HIF-1α mRNA decreased, but the protein expression increased[ 36 ]. m6A modification directly affected the translation efficiency of HIF-1α instead of the mRNA level[ 37 ].…”

m6A‐ and m5C‐ modified lncRNAs orchestrate the prognosis in cutaneous melanoma and m6A‐ modified LINC00893 regulates cutaneous melanoma cell metastasis

“…35 Li et al also showed that the inhibition of PVT1 exon 2 could induce the growth suppression of cutaneous squamous cell carcinoma, which was caused by cellular senescence, increased p21/CDKN1A expression and cell cycle arrest. 36 However, besides skin tumors, lncRNAs also influence the pathogenesis of many skin inflammatory diseases, 33 such as psoriasis, [38][39][40][41] hidradenitis suppurativa, 42,43 atopic dermatitis. [44][45][46] Among these skin diseases, the psoriasis was the most studied one.…”