Regulation and function of Myb-binding protein 1A (MYBBP1A) in cellular senescence and pathogenesis of head and neck cancer. Issue 2 (28th March 2015)

• Record Type: Journal Article
• Authors: George, Babitha; Horn, Dominik; Bayo, Pilar; Zaoui, Karim; Flechtenmacher, Christa; Grabe, Niels; Plinkert, Peter; Krizhanovsky, Valery; Hess, Jochen
• Is Part Of: Cancer letters. Volume 358:Issue 2(2015)
• Page Start: 191
• Page End: 199
• Publication Date: 2015-03-28
• Subjects: DNA damage -- Stress response -- Treatment failure -- Cancer; MYBBP1A Myb-binding protein 1A -- OPSCC oropharyngeal squamous cell carcinoma -- HNSCC head and neck squamous cell carcinoma -- SA-β-Gal senescence-associated β-galactosidase -- SAHF senescence-associated heterochromatic foci -- SASP senescence-associated secretory phenotype -- DDR DNA damage response -- PTEN phosphatase and tensin homolog -- NF1 neurofibromatosis Type1 -- VHL von Hippel–Lindau -- NFκB nuclear factor kappa B -- OS overall survival -- PFS progression free-survival; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.12.042
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: This is the first finding that demonstrates loss of MYBBP1A expression in tumor cells after DNA damage-induced senescence. Inverse correlation between MYBBP1A and pAKT(Ser473) after DNA damage represent a pre-senescent stage. MYBBP1A low pAKT(Ser473) high staining serves as an independent biomarker for an unfavorable clinical outcome of OPSCC patients. 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.