Synergistic epigenetics approaches to hamper the progression of hepatocellular carcinoma (HCC)
Project description:
The broader objective of this research project is to elucidate the role of a newly discovered epigenetic synergism between a histone variant called macroH2A1.1 and DNA hypomethylation in the onset and progression of metabolic stress-associated liver cancer (hepatocellular carcinoma, HCC), amidst the most aggressive types of cancer and leading causes of death worldwide. HCC occurrence and progression is strongly affected by obesity, intrahepatic fat content, and metabolic syndrome. Transcriptional changes associated with HCC insurgence are dependent on the plasticity of nuclear chromatin. Chromatin compaction is regulated at several levels, such as DNA methylation, post-translational modification of histones (acetylation, phosphorylation etc.) and replacement of canonical histones with histone variants. It is well known that HCC is characterized at the epigenetic level by a global DNA hypomethylation accompanied by a focal hypermethylation on the promoters of tumor suppressors, shunting their expression. MacroH2A1 is a histone variant of histone H2A, which can modulate transcription in cancer cells and regulate stem cell differentiation. MacroH2A1 is present in 2 isoforms, macroH2A1.1 and macroH2A1.2, generated upon alternative RNA splicing. MacroH2A1.1, unlike macroH2A1.2, is expressed ubiquitously, is protective against DNA damage and it regulates proliferative arrest in vitro. We have recently shown that HCCs express high levels of macroH2A1.1 and are refractory to cancer pro-senescence therapy upon treatment with DNA methyltransferase inhibitor 5-aza-deoxycytidine. Global hypomethylation and macroH2A1 overexpression are thus hallmarks of HCC. The aims of the project are:
•To understand in depth the interplay between macroH2A1.1 and DNA hypomethylation during hepatic metabolic stress-induced carcinogenesis in genetically modified murine models.
•To explore the therapeutic role of a new generation DNA hypomethylating agent, guadecitabine, against HCC and the epigenetic/transcriptional mechanisms involved.
These two objectives are attended using a combination of mouse genetics, cell culture models, biochemical and high-throughput sequencing approaches.
Scientists involved:
Manlio Vinciguerra, PhD, Senior Researcher (Scientific Coordinator)
Dr. Vinciguerra obtained his PhD in 2004 at the University of Geneva Medical School, Geneva, Switzerland. After 6 years of post-doctoral training between the University of Geneva and the European Molecular Biology Laboratory (EMBL, Heidelberg, Germany) he has covered PI positions at the IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, and at the University College London (UCL), London, UK. He joined Fondazione Italiana Fegato in 2016 as a Senior Researcher.
Period:
2016 - current
Funding:
AIRC (2012-2015)
Selected Publications:
Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Jueliger S, Lyons J, Cannito S, Pata I, Pata P, Shkolnaya M, Lo Re O, Peyrou M, Villarroya F, Pazienza V, Rappa F, Cappello F, Azab M, Taverna P, Vinciguerra M. Epigenetics. 2016 Aug 11:1-12.
DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, Mazzoccoli G, Faulkes C, Pata I, Agodi A, Rezaee F, Minogue S, Warren A, Peterson A, Sedivy JM, Douet J, Buschbeck M, Cappello F, Mazza T, Pazienza V, Vinciguerra M. Cancer Res. 2016 Feb 1;76(3):594-606. d
Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. McKee C, Sigala B, Soeda J, Mouralidarane A, Morgan M, Mazzoccoli G, Rappa F, Cappello F, Cabibi D, Pazienza V, Selden C, Roskams T, Vinciguerra M, Oben JA. Sci Rep. 2015 Mar 6;5:8812.
Hepatitis delta virus induces specific DNA methylation processes in Huh-7 liver cancer cells. Benegiamo G, Vinciguerra M, Guarnieri V, Niro GA, Andriulli A, Pazienza V. FEBS Lett. 2013 May 2;587(9):1424-8.
Liver diseases and aging: friends or foes? Sheedfar F, Di Biase S, Koonen D, Vinciguerra M. Aging Cell. 2013 Dec;12(6):950-4.
Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma. Rappa F, Greco A, Podrini C, Cappello F, Foti M, Bourgoin L, Peyrou M, Marino A, Scibetta N, Williams R, Mazzoccoli G, Federici M, Pazienza V, Vinciguerra M. PLoS One. 2013;8(1):e54458.
Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. Vinciguerra M, Carrozzino F, Peyrou M, Carlone S, Montesano R, Benelli R, Foti M. J Hepatol. 2009 Jun;50(6):1132-41.
