The Role of p300 Histone Acetyltransferase in UV-Induced Histone Modifications and MMP-1 Gene Transcription

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.

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…Furthermore, many posttranslational histone modifications have been shown to be modulated during the cellular response to DNA damage (Corpet and Almouzni, 2009;Kumar et al, 2012;Li et al, 2014;Tjeertes et al, 2009). For example, following UV exposure, the histone acetyltransferase p300 (also known as EP300) is recruited close to the MMP-1 promoter, regulating MMP-1 transcription by its catalytic activity (Kim et al, 2009). UV exposure induces phosphorylation of histone H3 serine 28 (H3S28p) at promoters of stress-response genes and causes dissociation of histone deacetylase (HDAC) co-repressor complexes that further accompanies enhanced levels of histone acetylation and transcriptional induction of these genes (Keum et al, 2013;Sawicka et al, 2014).…”

Epigenetic regulation of proMMP-1 expression in the HT1080 human fibrosarcoma cell line

“…It has been established that the proMMP-1 gene expression requires chromatin remodeling in part via histone posttranslational modifications (18)(19)(20)(21)(22). A previous study showed that proMMP-1 gene expression induced by TPA in T98G cells involved a dynamic and ordered recruitment of enzymes allowing H3/H4 acetylation, H3K4 di-and trimethylation, H3S10 phosphorylation and chromatin opening (22).…”

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies

“…It was shown that cellular stress could lead to matrix metalloproteinase-1 (MMP-1) induction and result in effects such as double-strand breaks of the DNA in human skin fibroblasts. 44 The same study demonstrated that AA successfully inhibited MMP-1 gene expression and subsequent apoptosis by inhibiting p300 HAT. We suppose that a similar mechanism plays a role in AA-mediated protection of NHDF against the cytotoxic activity of MIT.…”