Epigenetic modification mechanisms involved in keloid: current status and prospect

Abstract

Keloid, a common dermal fibroproliferative disorder, is benign skin tumors characterized by the aggressive fibroblasts proliferation and excessive accumulation of extracellular matrix. However, common therapeutic approaches of keloid have limited effectiveness, emphasizing the momentousness of developing innovative mechanisms and therapeutic strategies. Epigenetics, representing the potential link of complex interactions between genetics and external risk factors, is currently under intense scrutiny. Accumulating evidence has demonstrated that multiple diverse and reversible epigenetic modifications, represented by DNA methylation, histone modification, and non-coding RNAs (ncRNAs), play a critical role in gene regulation and downstream fibroblastic function in keloid. Importantly, abnormal epigenetic modification manipulates multiple behaviors of keloid-derived fibroblasts, which served as the main cellular components in keloid skin tissue, including proliferation, migration, apoptosis, and differentiation. Here, we have reviewed and summarized the present available clinical and experimental studies to deeply investigate the expression profiles and clarify the mechanisms of epigenetic modification in the progression of keloid, mainly including DNA methylation, histone modification, and ncRNAs (miRNA, lncRNA, and circRNA). Besides, we also provide the challenges and future perspectives associated with epigenetics modification in keloid. Deciphering the complicated epigenetic modification in keloid is hopeful to bring novel insights into the pathogenesis etiology and diagnostic/therapeutic targets in keloid, laying a foundation for optimal keloid ending.

Keywords: DNA methylation; Epigenetic modification; Histone modification; Keloid; ncRNAs.

Fig. 1

Schematic diagram of miRNA biogenesis and regulatory signaling pathways. MiRNAs are endogenous single-stranded RNAs with lengths of approximately 18–22 nucleotides. In the synthesis process of miRNAs, various enzymes are involved, including RNA polymerase, Drosha and Dicer enzymes, and Exportin-5 protein (a transporter protein). The pivotal role of mature miRNAs in regulating signaling pathways through binding to the 3′ untranslated region of the target mRNA, including PI3K/AKT signaling pathway and TGF-β signaling pathway. GTP: guanosine triphosphate; miRNA: microRNA; TRBP: TAR RNA binding protein

Fig. 2

Illustration of the main epigenetic mechanisms (DNA methylation, histone modifications, and ncRNAs) involved in the regulation of keloid progression including aberrant proliferation, myofibroblast activation, apoptosis, cell cycle, migration, and collagen production. DNMT: DNA methyltransferase; TET ten-eleven translocation, 5mC 5-methylated cytosine, 5fC 5-formylcytosine cytosine, 5-hmC 5-hydroxymethylated cytosine, 5caC 5-carboxylcytosine cytosine, TDG thymine DNA glycosylase, me methylation, ac acetylation, pho phosphorylation, ub ubiquitination, sum sumoylation