Enrico Desideri, PhD

E-Mail: enrico.desideri@univie.ac.at
Department of Microbiology, Immunobiology and Genetics

Project: "ALBA" - Regulation of protein acetylation by RAF1: impact on protein stability and liver carcinogenesis

Hepatocellular carcinoma (HCC) is the main liver malignancy and the third most common cancer death in men, with a growing incidence in the western world. Risk factors for the development of HCC include HBV and HCV infections, together with alcohol abuse and exposure to toxins (e.g. aflatoxin B1). However, the molecular mechanisms leading to HCC are still unknown, although inactivation of tumour suppressors and overexpression of oncogene has been documented. An event frequently observed in both clinical and experimental hepatocarcinogenesis is the increased expression of the transcriptional co-activator Yes-associated protein (YAP), which controls the expression of genes involved in cell cycle progression, cell proliferation and growth.

HCC usually develops as a consequence of liver injury and hepatocyte death followed by compensatory proliferation. Thus, pro- and antiapoptotic mechanisms are thought to contribute to the development of HCC. The transcription factor NF-kB, a pivotal regulator of cell survival, immune response and inflammation, is a case in point. In the mouse, reduced proteasomal degradation of the NF-kB inhibitor IkB causes spontaneous development of liver tumours. Investigating the mechanism controlling YAP and IkB expression will potentially indicate new avenues for molecular therapies.

Preliminary results from our lab revealed that RAF1 ablation in the liver increases the expression of a subset of proteins, including YAP and IkB-alpha without any effect on mRNA levels, suggestive of a regulation of protein stability. Both YAP and IkB-alpha stability is known to be regulated by post-translational modification (PTMs). However, beyond phosphorylation, little is known about other PTMs that can influence their stability, although a detailed understanding of these PTMs would provide a powerful tool to manipulate YAP and IkB-alpha levels for therapeutic purposes. Among PTM, lysine acetylation has been shown to modulate protein degradation via the two major protein degradation systems, autophagy (macroautophagy and chaperone-mediated autophagy) and the ubiquitin proteasome system (UPS). In line with this, preliminary results showed that YAP and IkB-alpha expression inversely correlates with their acetylation state. On this basis, the main aims of my project are: i) to evaluate whether and how acetylation influences YAP and IkB-alpha degradation by autophagy and UPS; and ii) to clarify the role of RAF1 in the control of protein acetylation.

Publications

  • Desideri E., Cavallo A.L. and Baccarini M. Alike but different: Raf isoforms and their signaling outputs. Cell. 2015; 161(5):967-970. doi: 10.1016/j.cell.2015.04.045.

  • Desideri E. and Ciriolo M.R. Glutamine addiction of cancer cells. Glutamine in Health and Disease. 2015 Humana Press – Elsevier USA.

  • Desideri E., Vegliante R., Cardaci S., Nepravishta R., Paci M., and Ciriolo M.R. MAPK14/p38-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation. Autophagy. 2014; 10:1652-65.

  • Desideri E., Vegliante R., Ciriolo M.R. Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle activity. Cancer Lett. 2014 Mar 12. pii: S0304-3835(14)00130-X. doi: 10.1016/j.canlet.2014.02.023.

  • Lettieri-Barbato D., Vegliante R., Desideri E., and Ciriolo M.R. Managing lipid metabolism in proliferating cells: new perspectives for metformin usage in cancer therapy. Biochim Biophys Acta. 2014 Feb 22. pii: S0304-419X(14)00019-5. doi:10.1016/j.bbcan.2014.02.003.

  • Desideri E., Filomeni G. and Ciriolo M.R. Glutathione participates in the modulation of autophagy in carcinoma cells. Autophagy 2012; 8(12):1769-81.

  • Desideri E. and Martins L.M. Mitochondrial Stress Signalling: HTRA2 and Parkinson's Disease. Int J Cell Biol 2012; 2012:607929.

  • Cardaci S., Desideri E. and Ciriolo M.R. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug. J Bioenerg Biomembr 2012; 44(1):17-29.

  • Filomeni G., Desideri E., Cardaci S., Rotilio G. and Ciriolo M.R. Under the ROS… Thiol network is the principal suspect for autophagy commitment. Autophagy 2010; 6(7):999-1005.

  • Filomeni G.*, Desideri E.*, Cardaci S., Piccirillo S., Graziani I., Rotilio G. and Ciriolo M.R. Carcinoma cells activate AMP-activated protein kinase-dependent autophagy as survival response to kaempferol-mediated energetic impairment. Autophagy 2010; 6(2):202-16.
    *equal contribution