title: Phosphorylation of p300 increases its protein degradation to enhance the lung cancer progression.
abstract: p300 is a transcription cofactor for a number of nuclear proteins. Most studies of p300 have focused on the regulation of its function, which primarily includes its role as a transcription co-factor for a number of nuclear proteins. In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. Inhibition of p300 degradation by blocking its phosphorylation decreased the proliferation and metastasis activity of lung cancer cells, indicating that p300 acts as a tumor suppressor in lung cancer tumorigenesis. Investigation of the molecular mechanism showed that blocking p300 phosphorylation disrupted chromatin condensation and the increased the acetylation of histone H3. Analysis of cell cycle progression in HA-p300-S2A-expressing cells by flow cytometry showed that the p300 mutants arrested the cells at S-phase or delayed the mitotic entry and exit. The expression of several important oncogenes, MMP-9, vimentin, β-catenin, N-cadherin and c-myc, was negatively regulated by p300. In conclusion, during lung tumorigenesis, a phosphorylation-mediated decrease in p300 level enhanced oncogene expression during interphase and decreased histone H3 acetylation during mitosis, which promoted lung cancer progression.
authors: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan.
authors: Shao-An
authors: SA
authors: Wang
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
authors: Chia-Yang
authors: CY
authors: Hung
authors: Neural Regenerative Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors: Jian-Ying
authors: JY
authors: Chuang
authors: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan; Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan; Center for Infectious Disease and Signal Transduction, National Cheng-Kung University, Tainan 701, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors: Wen-Chang
authors: WC
authors: Chang
authors: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan; Center for Infectious Disease and Signal Transduction, National Cheng-Kung University, Tainan 701, Taiwan.
authors: Tsung-I
authors: TI
authors: Hsu
authors: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan 701, Taiwan; Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan; Center for Infectious Disease and Signal Transduction, National Cheng-Kung University, Tainan 701, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: petehung@mail.ncku.edu.tw.
authors: Jan-Jong
authors: JJ
authors: Hung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D009361:Neoplasm Invasiveness; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D012333:RNA, Messenger; C556389:SCGB1A1 protein, human; D015534:Trans-Activators; D014598:Uteroglobin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D016203:CDC2 Protein Kinase
keywords: CDK1; Metastasis; Mitosis; Phosphorylation; Protein stability; p300