title: EGF-mediated inhibition of ubiquitin-specific peptidase 24 expression has a crucial role in tumorigenesis.
abstract: In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the KrasG12Dand EGFRL858Rmutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis. In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1-S transition and metaphase-anaphase transition. The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition. In conclusion, the USP24 level was decreased during the early stage of cancer and the mitotic stage of the cell cycle to regulate its substrates p300, Bax, E2F4 and securin, resulting in decreased cell apoptosis and increased cell cycle progression and, thus, cancer formation.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: S-A
authors.initials: SA
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Chuang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Su
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.|The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan.|Center for Infectious Disease and Signal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hung
mesh_terms: D000072283:A549 Cells; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics; D050704:E2F4 Transcription Factor / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D064249:Securin / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494826:BAX protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D064249:Securin; C513810:USP24 protein, human; D051028:bcl-2-Associated X Protein; C578002:pituitary tumor-transforming protein 1, human; D004815:Epidermal Growth Factor; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D043222:Ubiquitin Thiolesterase