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Regulation and function of MYBBP1A in cellular senescence and pathogenesis of head and neck cancer

George, Babitha

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Abstract

Myb-binding protein 1A (MYBBP1A) is a nucleolar protein implicated in stress response and carcinogenesis. However, its functional contribution to cellular senescence as well as the clinical relevance in head and neck squamous cell carcinoma (HNSCC) have not been addressed so far. In the present study, a cell culture model of genotoxic senescence, which was induced by the topoisomerase II inhibitor VP-16, was established to unravel the role of MYBBP1A in cellular senescence. Interestingly, in response to DNA damage, MYBBP1A first translocate from the nucleolus to the nucleoplasm and subsequently, its protein levels decreased in senescent cells. Loss-of-function approaches in tumor cell lines provided further evidence that silencing of MYBBP1A was not sufficient to trigger senescence, but that it modulated the efficacy of genotoxic-induced senescence and augments resistance to irradiation. Although, the precise molecular mechanism by which MYBBP1A regulates DNA damage-induced senescence remains elusive and warrants further investigation, this study revealed an inverse regulation of MYBBP1A and AKT(Ser473) phosphorylation to be a characteristic feature of senescent tumor cells. Most strikingly, immunohistochemical analysis of tissue microarrays with tumor specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) patients (n=61) revealed that a MYBBP1AlowpAKT(Ser473)high staining pattern serves as an independent marker for poor clinical outcome. Remarkably a significant correlation with progression-free or overall survival was not found considering pAKT(Thr308) levels, suggesting a more critical role of the mTOR/AKT pathway for the clinical behavior of OPSCCs with low MYBBP1A levels. In summary, these data demonstrate that tumor cells with a MYBBP1Alow but pAkt(Ser473)high protein pattern have a senescent-like phenotype and might critically contribute to tumor progression due to the emergence of highly malignant and/or therapy resistant tumor cells. Moreover, the abundance of MYBBP1AlowpAKT(Ser473)high senescent tumor cells in primary tumors as well as following tumor relapse could serve as a reliable biomarker for treatment decision making and to stratify HNSCC patients at high-risk for treatment failure. Thus, restoration of MYBBP1A function or pharmacological inhibition of the PI3K/mTOR/AKT pathway is an attractive new concept not only to sensitize tumor cells for available treatment options, but also to establish new strategies for targeted therapy with the potential of elimination of senescent cells.

Item Type: Dissertation
Supervisor: Hess, PD Dr. Jochen
Place of Publication: Heidelberg, Germany
Date of thesis defense: 18 June 2015
Date Deposited: 01 Jul 2015 08:48
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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