Securin PTTG protein stability by the balance between SUMO and Ub is responsible for its tumor over-expression and oncogenic action

TEDESCO, L.; ARZT, E.; SAPOCHNIK, M.; ATTORRESI, A.; FUERTES, M.; SENIN, S.

Cavtat-Dubrovnik

Conferencia; 2017 EMBO Conference Ubiquitin and SUMO: From molecular mechanisms to system-wide responses; 2017

European Molecular Biology Organization (EMBO)

Pituitary tumor transforming gene (PTTG) is a proto-oncogene that regulates cell cycle progression and has an increased expression in a wide variety of human solid tumors. Although the ubiquitin proteasome degradation of securin PTTG has been reported as required for complete chromatid separation, is not sufficient for the entire cell division including cytokinesis. Moreover, no mutations, epigenetic modifications or others mechanisms that explain PTTG high expression and action as oncogene have been described so far. By western blot and immunoprecipitation assays we describe increased stability of PTTG caused by sumoylation and regulated by the RWD-containing sumoylation enhancer (RSUME), which diminishes its degradation by the ubiquitin proteasome system and increases PTTG steady state levels. As a consequence, also we demonstrate in experiments in MEF cells that PTTG activity as securin and cell cycle regulator is altered resulting in recurrent and unequal divisions without cytokinesis and the appearance of aneuploidies and multinucleated cells. RSUME-knockdown destabilized PTTG and reduced its tumorigenic potential in a xenograft animal model. Additionally, we noticed that RSUME and PTTG are co-expressed in explants of different types of human pituitary tumors and these expression correlate significantly. Together, these results reveal the role of PTTG post-translational modifications for its oncogenic action and accounts for its abundance in cancer cells.