Acetylation in the regulation of metalloproteinase and tissue inhibitor of metalloproteinases gene expression.
Together, the matrix metalloproteinases (MMPs) are capable of degrading every component of the extracellular matrix (ECM). Besides degradation of the ECM, MMPs release bioactive molecules from the matrix or cell surface and play important role in tissue repair after injury, development and in a number of pathologies including arthritis and cancer metastasis. Small molecules that inhibit a broad spectrum of metalloproteinases have not proved useful in the treatment of various diseases, probably due to the diverse roles of this large family of enzymes. An alternative therapeutic approach for a number of pathologies is to modulate the expression of specific metalloproteinase genes. Acetylation represents a recently identified covalent protein modification that is strongly implicated in transcriptional regulation. Histones were the first proteins demonstrated to show variable acetylation leading to gene activation. Subsequently, a large number of molecules including structural proteins, intracellular signaling molecules, nuclear membrane receptors and transcription factors were shown to be acetylated. Acetylation, like phosphorylation, is a reversible modification. Acetyl groups are added by a family of histone acetyl transferase enzymes (HATs) and are removed by histone deacetylases (HDACs). Inhibitors of HDACs (HDACi) have potent anti-proliferative and pro-apoptotic activities in cancer cells and may be used as cancer therapeutics. In this review, we examine the impact of changes in acetylation on the expression of the MMPs and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs). We discuss the suggestion that HDACi may act in a dual fashion: selectively decreasing cancer cell viability and reducing metastatic potential by decreasing stromal cell expression of specific metalloproteinases. Furthermore, we consider the possibility that selective HDACi have a potential as anti-inflammatory agents and in a range of degradative diseases such as arthritis.
Clark
Ian M
IM
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom. i.clark@uea.ac.uk
Swingler
Tracey E
TE
Young
David A
DA
D000107:Acetylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014157:Transcription Factors; D020782:Matrix Metalloproteinases; D006655:Histone Deacetylases