Abstract
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 (γ-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 γ-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that γ-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 γ-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.
Highlights
Matrix metalloproteinase (MMP)-1, commonly known as interstitial collagenase, is able to cleave interstitial collagens [1]
The present study demonstrated that p300 histone acetyltransferase (p300HAT) mediates the UV induction of MMP-1 expression in human dermal fibroblasts (HDFs)
Our study indicated that UV irradiation stimulated the histone acetyltransferase (HAT) activity of p300 and led to increased histone acetylation, thereby relaxing chromatin structure and promoting MMP-1 activation
Summary
Matrix metalloproteinase (MMP)-1, commonly known as interstitial collagenase, is able to cleave interstitial collagens [1]. It belongs to a superfamily of zinc-dependent endopeptidases that are capable of degrading extracellular matrix components [2]. Excessive damage of connective tissue involves destruction of functional tissue structure, as in rheumatoid arthritis, osteoarthritis, autoimmune blistering disorders of skin, and dermal photoaging [5,6,7]. UV radiation is a major exogenous toxic agent [9] that leads to cellular damage and effects such as sunburn, immune suppression, skin cancer and photoaging [10]. The cellular response to DNA damage by UV radiation involves specific repair pathways such as nucleotide excision repair (NER). The stabilization and transactivation of p53 in response to DNA damage may be mediated through CBP/p300 [14] and/or PCAF [15,16]
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