title: TAK1 ubiquitination regulates doxorubicin-induced NF-κB activation.
abstract: Chemotherapeutic agents- and radiation therapy-induced NF-κB activation in cancer cells contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. TAK1 has been shown to be required for genotoxic stress-induced NF-κB activation. However, whether TAK1 ubiquitination is involved in genotoxic stress-induced NF-κB activation remains unknown. Herein, we demonstrate that TAK1 ubiquitination plays an important role in the positive and negative regulation of doxorubicin (Dox)-induced NF-κB activation. We found that TAK1 was required for Dox-induced NF-κB activation. At the early stage of Dox treatment, Dox induced Lys63-linked TAK1 polyubiquitination at lysine 158 residue. USP4 inhibited Dox-induced TAK1 Lys63-linked polyubiquitination and knockdown of USP4 enhanced Dox-induced NF-κB activation. At the late stage of Dox treatment, Dox induced Lys48-linked TAK1 polyubiquitination to promote TAK1 degradation. ITCH inhibited Dox-induced NF-κB activation by promoting Lys48-linked TAK1 polyubiquitination and its subsequent degradation. Our study indicates that TAK1 ubiquitination plays critical roles in the regulation of Dox-induced NF-κB activation. Thus, intervention of TAK1 kinase activity or TAK1 Lys63-linked polyubiquitination pathways might greatly enhance the therapeutic efficacy of Dox.
authors.affiliation: Department of Tumor Chemotherapy and Radiation Sickness in Peking University Third Hospital, Beijing 100191, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.forename: Da
authors.initials: D
authors.lastname: Cheng
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Baoshan
authors.initials: B
authors.lastname: Cao
authors.forename: Liwen
authors.initials: L
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Xu
authors.initials: X
authors.lastname: Su
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D012097:Repressor Proteins; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C486203:USP4 protein, human; C432966:ITCH protein, human