title: The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice.
abstract: The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Program in Molecular Structure and Function, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada;
authors.forename: Jiefei
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China;
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Juan
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, ON, Canada;
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Program in Molecular Structure and Function, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada;
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Mayo Clinic, Scottsdale, AZ;
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.affiliation: Department of Hematology, Changzheng Hospital, The Second Military Medical University, Shanghai, China; and.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Hematology, Changzheng Hospital, The Second Military Medical University, Shanghai, China; and.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China;
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Mayo Clinic, Scottsdale, AZ;
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Department of Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, ON, Canada;
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Program in Molecular Structure and Function, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada;
authors.forename: Michael F
authors.initials: MF
authors.lastname: Moran
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D025801:Ubiquitin; C525952:HERC4 protein, mouse; D044767:Ubiquitin-Protein Ligases