Role of the SIRT7/NPM pathway in lung cancer progression

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Lung cancer is the second cause of death due to malignancy and around 85% of the diagnosed patients display a histological subtype collectively known as non-small cell lung cancer (NSCLC). Lung tumors are very aggressive and the prognosis of diagnosed patients is very poor. Thus, unveiling the molecular mechanisms underlying lung tumorigenesis is imperative for development of novel therapeutical approaches. SIRT7 is the least investigated member of the family of mammalian sirtuins, a class of histone/protein deacetylases involved in different steps of tumorigenesis. Recently, we discovered that SIRT7 interacts with and deacetylates the nucleolar protein nucleophosmin (NPM) to promote NPM-mediated stabilization of the tumor suppressor p53 following genotoxic stress. NPM plays also critical roles in cancer progression. Our preliminary data demonstrate that SIRT7 represses several tumor suppressive functions of NPM, most prominently the stabilization of the tumor suppressor ARF and NPM-mediated inhibition of the proto-oncogene c-Myc in lung cancer cells. In the proposed project, we aim to characterize the impact of SIRT7 activities in lung tumorigenesis through NPM-dependent and –independent mechanisms both in vitro and in vivo. We believe that the proposed project will lead to identification of novel molecular pathways sustaining lung cancer progression that could be targeted for development of innovative anti-cancer drugs.