title: Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression.
abstract: Sex-determining region Y box 6 (SOX6) has been described as a tumor-suppressor gene in several cancers. Our previous work has suggested that SOX6 upregulated p21(Waf1/Cip1)(p21) expression in a p53-dependent manner; however, the underlying mechanism has remained elusive. In this study, we confirmed that SOX6 can suppress cell proliferation in vitro and in vivo by stabilizing p53 protein and subsequently upregulating p21. Co-immunoprecipitation and immunocytofluorescence assays demonstrated that SOX6 can promote formation of the p14ARF-HDM2-p53 ternary complex by promoting translocation of p14ARF (p14 alternate reading frame tumor suppressor) to the nucleoplasm, thereby inhibiting HDM2-mediated p53 nuclear export and degradation. Chromatin immunoprecipitation combined with PCR assay proved that SOX6 can bind to a potential binding site in the regulatory region of the c-Myc gene. Furthermore, we confirmed that SOX6 can downregulate the expression of c-Myc, as well as its direct target gene nucleophosmin 1 (NPM1), and that the SOX6-induced downregulation of NPM1 is linked to translocation of p14ARF to the nucleoplasm. Finally, we showed that the highly conserved high-mobility group (HMG) domain of SOX6 is required for SOX6-mediated p53 stabilization and tumor inhibitory activity. Collectively, these results reveal a new mechanism of SOX6-mediated tumor suppression involving p21 upregulation via the p14ARF-HDM2-p53 axis in an HMG domain-dependent manner.
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medicine, Peking University Health Science Center, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Lu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D000090243:Nucleophosmin; D017434:Protein Structure, Tertiary / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D055755:SOXD Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000493:pharmacokinetics* / Q000502:physiology*
chemical_list: C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; D051736:Proto-Oncogene Proteins c-mdm2