title: An IKKα-nucleophosmin axis utilizes inflammatory signaling to promote genome integrity.
abstract: The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKKα promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by genomic instability, including aneuploid chromosomes and extra centrosomes. In this study, we found that IKKα promoted oligomerization of nucleophosmin (NPM), a negative centrosome duplication regulator, which further enhanced NPM and centrosome association, inhibited centrosome amplification, and maintained genome integrity. Levels of NPM hexamers and IKKα were conversely associated with skin tumor progression. Importantly, proinflammatory cytokine-induced IKKα activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKKα blocked this connection. Therefore, our findings suggest a mechanism in which an IKKα-NPM axis may use inflammatory signals to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression.
authors.affiliation: Department of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xia
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Zuoxiang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Song
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Unit 389, Smithville, TX 78957, USA.
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Unit 389, Smithville, TX 78957, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Advanced Technology Program, Electron Microscopy Laboratory, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkett
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Datla
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Jami
authors.initials: J
authors.lastname: Willette-Brown
authors.affiliation: Department of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. Electronic address: huy2@mail.nih.gov.
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D016466:CHO Cells; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016678:Genome; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D055503:Protein Multimerization; D015398:Signal Transduction
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051550:I-kappa B Kinase