title: USP4 inhibits p53 and NF-κB through deubiquitinating and stabilizing HDAC2.
abstract: Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. As HDACs are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. In this study, we show that ubiquitin-specific peptidase 4 (USP4) interacts directly with and deubiquitinates HDAC2, leading to the stabilization of HDAC2. Accumulation of HDAC2 in USP4-overexpression cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation and apoptotic response upon DNA damage. Moreover, USP4 targets HDAC2 to downregulate tumor necrosis factor TNFα-induced nuclear factor (NF)-κB activation. Taken together, our study provides a novel insight into the ubiquitination and stability of HDAC2 and uncovers a previously unknown function of USP4 in cancers.
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, China.|Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, China.|Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, China.|Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiong
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Zhongshan Hospital Xiamen University, Xiamen, China.
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.affiliation: Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: L
authors.initials: L
authors.lastname: Gu
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lv
authors.affiliation: Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D015972:Gene Expression Regulation, Neoplastic; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C486203:USP4 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D056464:Histone Deacetylase 2