Histone acetylation involves in the increased expression of prosurvival molecules induced by photodynamic therapy: mechanistic investigation and clinical implication
Date Issued
2015
Date
2015
Author(s)
Tsai, Yi-Jane
Abstract
Oxidative stress induced by photodynamic therapy (PDT) mediates the tumoricidal effect, but has also been shown to induce the expression of pro-survival molecules, such as cyclooxygenase-2 (COX-2), which are involved in tumor recurrences after PDT. However, the molecular mechanism is still not fully understood. In this study, we found that PDT-induced p38MAPK activation could significantly up-regulate the activity and expression of histone acetyltransferase p300 (p300HAT) in A375 and C26 cells under ALA or chlorin e6 (Ce6) mediated photodynamic treatment. Colony-formation assay showed PDT-induced cytotoxicity was dramatically elevated in the presence of p300HAT inhibitor, anacardic acid (AA). Further studies showed that the increased p300HAT can transfer the acetyl group to histone H3 and NF-κB p65 subunit to up-regulate the COX-2 expression. The effect was reduced by the shRNA of AA or p300HAT. Using chromatin immunoprecipitation analysis, we found that the acetylation of histone H3 and NF-κB increases their binding to the COX-2 promoter region. These findings were further verified in the in vivo xenograft mouse model bearing murine C26 and human A375 tumors treated with PEGylated Liposome Ce6 (PL-Ce6) mediated PDT. Meanwhile, the combination of PDT and AA resulted in a greater tumor regression in BALB/c mice bearing C26 tumors, compared to those treated with PDT only or combined with COX-2 inhibitor. Finally, we demonstrated that suppression of the PDT-induced p300HAT activity also resulted in the decreased expression of survivin, restoring caspase-3 activity and sensitizing PDT-treated cells from autophagy to apoptosis due to the Becline-1 cleavage. This study demonstrates that the molecular mechanisms involved in histone modification induced by PDT-mediated oxidative stress, suggesting that HAT inhibitors may provide a novel therapeutic approach for improving PDT response.
Subjects
Photodynamic therapy
Histone acetylation
Histone acetyltransferase
Type
thesis
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