title: Regulation and function of Myb-binding protein 1A (MYBBP1A) in cellular senescence and pathogenesis of head and neck cancer.
abstract: Myb-binding protein 1A (MYBBP1A) is a nucleolar protein implicated in stress response and carcinogenesis; however, its functional contribution to senescence remains elusive. In this study we show decreased MYBBP1A protein levels in tumor cells after treatment with etoposide, a potent inducer of DNA damage. Although silencing of MYBBP1A expression was not sufficient to induce senescence, it significantly increased the relative abundance of senescent cells after DNA damage. We found an inverse regulation of MYBBP1A and AKT phosphorylation (pAKT(Ser473)), which was characteristic for the pre-senescent state after etoposide administration in vitro. Tissue microarrays with tumor specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 61) by immunohistochemistry revealed a significant correlation between MYBBP1A(low)pAKT(Ser473)(high) staining pattern and shorter progression-free (p = 0.007) or overall survival (p < 0.001). Multivariate analysis showed that MYBBP1A(low)pAKT(Ser473)(high) staining pattern is an independent prognosticator for OPSCC. Taken together, our study points to a critical role of MYBBP1A in the regulation of senescence under genotoxic stress and that a MYBBP1A(low)AKT(Ser473)(high) staining pattern serves not only as a marker for the pre-senescent stage but also as an indicator of OPSCC patients at high risk for treatment failure.
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Babitha
authors.initials: B
authors.lastname: George
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany; Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Horn
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Pilar
authors.initials: P
authors.lastname: Bayo
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Zaoui
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, Heidelberg, Germany; Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Plinkert
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Valery
authors.initials: V
authors.lastname: Krizhanovsky
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: Jochen.Hess@med.uni-heidelberg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt
keywords: Cancer; DNA damage; Stress response; Treatment failure