The role of p300 histone acetyltransferase in UV-induced histone modifications and MMP-1 gene transcription.
Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (gamma-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced gamma-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that gamma-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (-2067/-1768) adjacent to the p300 binding site (-1858/-1845) in the MMP-1 promoter. In addition, these recruitments of gamma-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV.
Kim
Min-Kyoung
MK
Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
Shin
Jung-Min
JM
Eun
Hee Chul
HC
Chung
Jin Ho
JH
D001483:Base Sequence; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology* / Q000528:radiation effects; D006657:Histones / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000502:physiology* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D017931:DNA Primers; D006657:Histones; D020781:Matrix Metalloproteinase 1; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor