The therapeutic role of histone deacetylase inhibitors in keloids

Keloids are benign fibro-proliferative scars which express cancer-like properties such as an increased cellular proliferation, migration, and invasion. The main challenge keloids present is their high recurrence rates and resistance to current treatments. Meanwhile, histone deacetylase inhibitors (HDI) have shown promise in treating various cancers through inhibiting proliferation and inducing apoptosis. Additionally, HDIs have also been shown to be effective in treating fibrotic diseases such as renal fibrosis through modulating gene expression by increasing acetylation of histones as well as non-histone targets such as the transcription factor STAT3. As such, we hypothesize that HDI is therapeutic in treating keloids via increasing acetylation of histone proteins and STAT3. Using MTT assay, we found that HDI treatment led to a decrease in keloid fibroblast (KF) viability at dosages that normal fibroblasts can tolerate. This highlights an increased sensitivity of KF to HDI treatment, demonstrating the potential in using HDI as keloid therapy. We further confirmed this using wound healing assay to determine HDI efficacy. We found that when treated with HDI, migration rate of fibroblasts was inhibited. Furthermore, we demonstrated via RT-PCR that HDI treatment suppressed collagen and fibronectin gene expression in KFs. Next, we determined the mechanism of action of HDI through western blot and found that both histone H2B and H4 acetylation increased after KF were treated with HDIs. Furthermore, acetylation of transcription factor STAT3 also increased, corresponding with reduced collagen and fibronectin protein levels. We concluded that histone deacetylase inhibition ameliorates fibrosis in keloids disease via inducing histone and STAT3 acetylation.