Novel regulation of human myometrial contractility by histone deacetylase 8 (HDAC8)

Approximately 6-10% of human pregnancies end with delivery before ?full term?, and premature born babies suffer from long term physical and mental handicap. Furthermore, up to 65% of perinatal births are related to premature birth. To date, drugs used to stop contractions, termed tocolytics, are still not effective and safe enough and cause non-specific and often dangerous side effects for both mother and infant. Recent investigations on vascular smooth muscle cells has indicated that a specific protein histone deacetylase 8 (HDAC8) is a specific marker of smooth muscle and is essential for the contractility of this muscle cell type. Our initial data also indicates that this protein may play an important role in regulating uterine smooth muscle activity during pregnancy and labour. Consequently the purpose of the research proposal are to define whether this is the case and to determine whether highly selective HDAC8 inhibitors can act as potential novel therapeutic agents in the better management of premature labour.

It is now becoming increasingly recognized that regulation of proteins by acetylation on lysine residues may be a key effector in regulating their activity and that histone deacetylases (HDACs) play a pivotal role in this process. In this respect the epigenetic effects of inhibitors on gene expression via increased histone acetylation and chromatin remodeling are now well known. However, growing evidence also indicates that non-histone proteins are additional targets for HDACs. Recently, HDAC8, a member of the predominantly nuclear bound family of class I HDACs, has been found to be a cytosolic marker of smooth muscle differentiation and associates with the cytoskeleton-protein smooth muscle alpha-actin in human vascular smooth muscle cells and is essential for its contractility. In this respect our pilot studies in human myometrial smooth muscle cells has demonstrated that HDAC8 is also present in these cells and is localised predominantly in the cytoplasmic/cytoskeletal region rather than in the nucleus in contrast to HDAC1. Consequently the goals of the research proposal are to define whether HDAC8 plays an important role in regulating the contractile machinery in the myometrium and to define whether highly selective HDAC8 inhibitors can perturb this mechanism and thus act as potential tocolytics.