HNRNPC Promotes Keloid Progression by Modulating the Stability of N-Methyladenosine-Modified WDR77 mRNA and Expression of TGF-β and SMAD3.

Abstract

Keloid is a cutaneous fibrotic disorder distinguished by uncontrolled dermal fibroblast proliferation and accumulation of collagen. N-methyladenosine (MA) modification is the most prevalent epitranscriptomic modification of eukaryotic mRNAs. MA modification participates in a variety of biological processes of cells by influencing the stability, translation efficiency, splicing, and transport of mRNAs. Recently, mA modification in keloids has garnered interest but is not fully understood. In this study, we discovered that keloids were in hyper-mA-modified status, and HNRNPC was overexpressed in keloid tissues and keloid fibroblasts. The knockdown of HNRNPC inhibited the migration and proliferation of keloid fibroblasts. Through RNA immunoprecipitation PCR and luciferase experiments, WDR77 was identified as an mA-dependent direct downstream target of HNRNPC. Furthermore, HNRNPC promoted the expression of WDR77 by increasing WDR77 stability, elevating the expression of TGF-β and SMAD3. In keloid xenograft nude mice, HNRNPC small interfering RNAs significantly limited keloid development with reduced WDR77 and TGF-β expression. Thus, our study revealed that HNRNPC regulated the pathological functions of keloid fibroblasts through the mA methylation of WDR77 mRNA and that the inhibition of HNRNPC limited keloid progression in vivo. Our results decipher an mA-related mechanism and potential therapeutic strategy for combating keloids.