Embryonic development and postnatal renewal of the epidermis and hair follicles require coordinated changes in gene expression that are often dysregulated in tumorigenesis. Histone deacetylases (HDACs) provide global control of gene expression programs by repressive modification of chromatin, and form several classes, of which Class 1 members display the highest histone deacetylase activity. Of these, HDACs 1 and 2 associate with Mi2?, MTA-2 and MDB3 in the NuRD complex and with Sin3, SAP18 and SAP30 in the Sin3 complex, while HDAC3 complexes with N-CoR or SMRT. HDAC inhibitors (HDACi) are promising therapeutic agents for multiple types of tumor. However, while the functions and targets of individual HDACs vary widely, most HDACi broadly inhibit Class 1 HDACs, and their precise mechanisms of action are poorly understood. The goals of this proposal are to use genetic, biochemical, and global genomic approaches to delineate and compare the functions of HDAC1, HDAC2 and HDAC3 in the development and regeneration of skin epithelia, to identify transcription factors that target individual HDACs to specific sets of promoters in skin epithelial cells, and to determine the consequences of deletion of Hdac1, 2 or 3 for the initiation and progression of epidermal tumors. Data from these experiments will be critical for evaluating the potential risks and benefits of targeting individual HDACs in the epidermis and for developing more specific and effective therapeutics.
Epidermal development requires broad changes in gene expression that are orchestrated by chromatin remodeling factors such as histone deacetylases (HDACs). Conversely, tumorigenesis involves suppression of differentiation programs and reversion to an embryonic-like state, raising interest in HDACs as potential therapeutic targets. The goal of this proposal is to evaluate the therapeutic benefits and potential risks of targeting HDAC1, HDAC2 and HDAC3 in the epidermis by establishing their roles and mechanisms of action in normal development and postnatal homeostasis, and determining the effects of their deletion in mouse models for the two most common epidermal tumors, basal cell carcinoma and squamous cell carcinoma.