title: Histone acetyltransferase p300 is induced by p38MAPK after photodynamic therapy: the therapeutic response is increased by the p300HAT inhibitor anacardic acid.
abstract: Oxidative stress mediated by photodynamic therapy (PDT) mediates the tumoricidal effect, but has also been shown to induce the expression of prosurvival molecules, such as cyclooxygenase-2 (COX-2), which is involved in tumor recurrences after PDT. However, the molecular mechanism is still not fully understood. In this study, we found that activated p38MAPK could significantly up-regulate the activity and expression of histone acetyltransferase p300 (p300HAT) in A375 and C26 cells treated with ALA-and chlorin e6 (Ce6)-mediated photodynamic treatment. A colony-formation assay showed that PDT-induced cytotoxicity was dramatically elevated in the presence of the p300HAT inhibitor anacardic acid (AA). Further studies showed that increased p300HAT acetylates histone H3 and NF-κB p65 subunit to up-regulate the COX-2 expression, which was reduced by AA or p300HAT shRNA. Using chromatin immunoprecipitation analysis, we found that the augmented acetylation of histone H3 and NF-κB increases their binding to the COX-2 promoter region. These in vitro findings were further verified in mice bearing murine C26 and human A375 tumors treated with liposomal Ce6 mediated PDT. Meanwhile, the combination of PDT and AA resulted in greater tumor regression in BALB/c mice bearing C26 tumors, compared 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 for the first time 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.
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Yi-Jane
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Biomedical Materials and Tissue Engineering, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Tsuimin
authors.initials: T
authors.lastname: Tsai
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Peng
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Pei-Tzu
authors.initials: PT
authors.lastname: Li
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan. Electronic address: chintin@ntu.edu.tw.
authors.forename: Chin-Tin
authors.initials: CT
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D048729:Anacardic Acids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002735:Chlorophyllides; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010778:Photochemotherapy; D011166:Porphyrins / Q000008:administration & dosage*; D011499:Protein Processing, Post-Translational; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D048729:Anacardic Acids; D000970:Antineoplastic Agents; D002735:Chlorophyllides; D051546:Cyclooxygenase 2; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D051996:Transcription Factor RelA; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099224:p300-CBP-Associated Factor; C498143:RELA protein, human; C088115:anacardic acid; C062985:phytochlorin; C496540:PTGS2 protein, human
keywords: COX-2; Histone acetylation; Histone acetyltransferase; Photodynamic therapy; Survivin