Role of the SIRT7-NPM-c-Myc pathway in lung cancer

Lung cancer is the second cause of death due to malignancy and diagnosed patients rarely survive beyond two years.

Thus, unveiling the molecular mechanisms underlying lung tumorigenesis is imperative for development of novel therapeutic approaches.

The nucleolar protein nucleophosmin (NPM) plays critical roles in cancer progression and is often deregulated in human malignancies.

NPM employs distinct mechanisms to control cancer cells growth including regulation of the proto-oncogene c-Myc, a transcription factor often aberrantly activated in lung cancer. Recent studies highlighted the fundamental impact of post-translational modifications in controlling NPM functions.

NPM is a deacetylation target of Sirtuin 7 (SIRT7), a member of a class of NAD+ dependent histone/protein deacetylases collectively known as sirtuins.

Deacetylation of NPM by SIRT7 is fundamental to control NPM subcellular localization and stimulate NPM-mediated cellular stress responses. SIRT7 also acts as a potent oncogene in different malignancies although through still poorly characterized mechanisms.

Thus, SIRT7-LC aims to characterize the impact of the SIRT7-NPM axis on regulation of c-Myc pro-oncogenic activities and its impact on lung cancer cells proliferation in vitro and in vivo, as well as possible aberrant activation of this pathway in human lung cancers and its correlation with prognosis.

Thus, SIRT7-LC may lead to identification of novel molecular mechanisms sustaining lung cancer growth that could be targeted for therapeutic interventions. Dr. Alejandro Vaquero, a world-leading expert in the sirtuins field, will supervise this project.

His competence in the field together with my expertise in characterization of mouse models of diseases will undoubtedly ensure successful realization of the proposed project, expanding my scientific knowledge, increasing my visibility as scientist and contributing to my development as a fully independent investigator.