Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5

Abstract

Diabetic foot ulcers (DFUs), a life-threatening complication of diabetes mellitus, have limited treatment options, often resulting in amputations. HMG-CoA reductase inhibitors such as statins are cholesterol-reducing agents that may provide a new therapeutic option. Statins target the cholesterol pathway and block the synthesis of the wound-healing inhibitors farnesyl pyrophosphate (FPP) and cortisol, ligands for the glucocorticoid receptor (GR). Here we demonstrate that the naturally occurring statin mevastatin reverses FPP's effects and promotes healing by using wound healing assays, human and porcine wound models, and DFU tissue. Moreover, we measured cortisol levels by ELISA and found that mevastatin inhibited cortisol synthesis in keratinocytes and biopsies from patients with DFU. Of note, topical mevastatin stimulated epithelialization and angiogenesis Mevastatin also reversed FPP-mediated induction of the GR target, the transcription factor c-Myc (a biomarker of non-healing wounds), in porcine and human wound models. Importantly, mevastatin reversed c-Myc overexpression in DFUs. It induced expression of the long noncoding RNA Gas5 that blocks c-Myc expression, which was confirmed by overexpression studies. We conclude that topical mevastatin accelerates wound closure by promoting epithelialization via multiple mechanisms: modulation of GR ligands and induction of the long noncoding RNA Gas5, leading to c-Myc inhibition. In light of these findings, we propose that repurposing statin drugs for topical treatment of DFUs may offer another option for managing this serious condition.

Long noncoding RNA GAS5 does not regulate HBV replication

“…GAS5 played significant roles in diverse cellular processes through mediating cell cycle, apoptosis, autophagy, drug resistance, or inflammatory response . Since GAS5 is located both in nuclear and cytoplasm, it exerts molecular mechanisms by acting as riborepressor to block the activation of target gene transcription (eg, c‐Myc) . Also, it can function as a ceRNA through different signaling axes (eg, miR‐222/PTEN/Akt/mTOR and miR‐21/PTEN/MMP‐2), modulates gene transcription via interacting with transcriptional factors (eg, E2F1), or directly controls gene translation (eg, NS3) .…”

Long noncoding RNAs in autoimmune diseases

“…The study suggested that deletion of the Sp1-binding site in the promoter region of GAS5 leads to downregulation of GAS5 expression, thereby inhibiting apoptosis and resulting in autoantigen exposure and the production of autoantibodies. 27,28,71 Researchers have found that the silencing of nuclear enriched abundant transcript 1 (lncRNA NEAT1) can significantly reduce the expression of a group of chemokines and cytokines, including interleukin 6 (IL-6) and CXCL10. NEAT1 expression is induced by lipopolysaccharide via activation of p38 and is higher in the peripheral blood cells of SLE patients than in healthy individuals.…”

“…Further research found that Gas5 binds to the DNA‐binding domain of GR by acting as a decoy GRE, thus competing with DNA GREs for binding to GR. The study suggested that deletion of the Sp1‐binding site in the promoter region of GAS5 leads to downregulation of GAS5 expression, thereby inhibiting apoptosis and resulting in autoantigen exposure and the production of autoantibodies …”

Glucocorticoid Receptor Signaling in Skin Barrier Function

“…The activation of GR by cortisol or FPP caused nuclear translocation of β-catenin, leading to induction of c-myc, a hallmark of chronic nonhealing wounds. This led to the proposal to use statins to restore epidermal homeostasis as targeting the cholesterol pathway interferes with the production of FPP and cortisol, resulting in substantial reduction of GR activation, and c-myc downregulation [89]. It has also been shown that GCs can also inhibit keratinocyte migration and wound healing by activation of nongenomic signaling pathways involving membrane GR regulation of phospholipase C/protein kinase C ultimately activating β-catenin and c-myc [90].…”