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.

Targeted inhibition of YAP/TAZ alters the biological behaviours of keloid fibroblasts

“…Multiple studies have shown that keloid‐derived fibroblasts undergo increased proliferation, increased migration and reduced apoptosis 2,25 . In isolated culture cells, we demonstrate that keloid fibroblasts express high levels of YAP/TAZ mRNA and protein compared to normal skin fibroblasts.…”

A Signature of Nine lncRNA Methylated Genes Predicts Survival in Patients With Glioma

“…In addition, promoter regulation and gene quantification can also affect the overall expression level of lncRNAs ( 44 , 45 ). Epigenetic regulation of lncRNAs has been suggested to be an important mechanism contributing to tumor progression ( 46 ). Among them, lncRNA expression could be influenced by changes in the methylation level of its promoter or enhancer region, thus promoting the malignant progression of glioma.…”

Activating transcription factor 3 (ATF3) regulates cell growth, apoptosis, invasion and collagen synthesis in keloid fibroblast through transforming growth factor beta (TGF-beta)/SMAD signaling pathway

“…Flow cytometric analysis showed that ectopic expression of ATF3 significantly reduced the numbers of apoptotic cells compared to that of the control group, while inhibition of ATF3 increased the apoptotic rate of keloid fibroblast cells ( Figure 3 ). In addition, we evaluated the mRNA and protein levels of apoptosis-related genes, including BCL2, Bad, Caspase3 and Caspase9 [ 18 ], in keloid fibroblast cells. Consistently, real-time PCR analysis showed that ATF3 up-regulation significantly promoted BCL2 mRNA and inhibited mRNA levels of Bad, Caspase3 and Caspase9 ( Figure 4(a-d) ) in keloid fibroblast cells.…”