Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita.

Abstract

Pachyonychia congenita (PC) is a keratinizing disorder predominantly caused by mutations in keratin 6a (K6a) (∼50% of cases) or K6b, K16, or K17. One means of treating PC is identification of small-molecule inhibitors of PC-related keratins. Here, we cloned the human K6a promoter, and using a cell-based reporter gene assay, a chemical library was screened for K6a inhibitors. One compound, compactin, the precursor of all cholesterol-lowering statins, was of particular interest. We found that, surprisingly, simvastatin and other statins inhibit K6a promoter activity and K6a protein expression. Further investigation showed that this effect works through cholesterol/mevalonate pathway inhibition rather than an off-target effect. Inhibition of both basal and IFN-γ-inducible K6a expression by statins was demonstrated. Both these K6a inhibitory effects were found to be mediated by Stat1 transcription factor, but only the IFN-γ-inducible promoter activity was controlled via the Stat/JAK pathway. The repressive effect of statins was found to be mediated by the isoprenoid pathway downstream of mevalonate (the intermediate following 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) but upstream of cholesterol, specifically the geranylgeranylation pathway. These data set the scene for further unraveling signaling pathways that control the K6a promoter, as well as facilitating clinical trials for statins in PC patients.

• Authors: Yiwei Zhao, Ulrike Gartner, Frances J D Smith, W H Irwin McLean
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 131 Issue 5 Pg. 1045-52 (May 2011) ISSN: 1523-1747 [Electronic] United States
• PMID: 21390048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• KRT6A protein, human
• Keratin-6
• STAT1 Transcription Factor
• STAT1 protein, human
• mevastatin
• Interferon-gamma
• Lovastatin
• Mevalonic Acid

Topics

• Anticholesteremic Agents (therapeutic use)
• Cell Line
• Down-Regulation
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Interferon-gamma (pharmacology)
• Keratin-6 (antagonists & inhibitors, genetics)
• Lovastatin (analogs & derivatives, therapeutic use)
• Mevalonic Acid (antagonists & inhibitors)
• Pachyonychia Congenita (drug therapy)
• Promoter Regions, Genetic (drug effects)
• STAT1 Transcription Factor (pharmacology)