Ablation of epidermal HDAC3 and HDAC4 protects against chemically-induced skin tumorigenesis in mice

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Conference Proceeding

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Publication Title

J Invest Deramtol


Overexpression of histone deacetylases (HDACs) are correlated with malignancy in both patients and experimental animals. HDAC3 and HDAC4, which are highly expressed in cutaneous epidermal cells, are positively associated with a variety of solid tumors and show synergic catalytic activity when forming a complex together. However, the specific roles for HDAC3 and HDAC4 in cutaneous biology and tumorigenesis have yet to be fully elucidated. In this study, we generated keratinocyte-specific HDAC3 and HDAC4 knockout (KO) mice which underwent 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) induced carcinogenesis along with wild-type (WT) littermate controls. KO mice had no apparent cutaneous morphological changes but did exhibit significantly extended tumor latency and decreased tumor incidence/multiplicity compared to WT controls in DMBA/TPA-induced skin carcinogenesis. HDAC3/4 deletion-mediated tumor protection was associated with inhibition of cellular proliferation and cell cycle progression in the epidermis. Furthermore, skin tumors from KO mice displayed enhanced expression of skin tumor suppressors, p21 and p53; and down-regulated expression of tumor promoters, c-Myc and NF-eˆB p65. Together, our data implicate HDAC3 and HDAC4 as mediators of cutaneous tumorigenesis and suggest HDAC3/4 may serve as therapeutic targets in cutaneous tumors.




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