THE CITRATE, AN ACETYL DONOR ABLE TO INHIBIT THE HISTONE ACETYLATION

Citrate is an intermediate in the Krebs cycle and an acetyl donor. Due to its ability to inhibit glycolysis, a very active metabolic pathway in tumors, it has been proposed as an anticancer agent(1). Several studies support this activitiy. Cytosolic citrate is processed by ATP citrate lyase to produce cytosolic acetyl CoA, which sustains the histone acetylation and the cell proliferation by lipid synthesis (2). Cancer cells exhibit reprogrammed metabolic pathways to support bioenergetic, biosynthetic, and redox demands (3). Cancer cells have a reduced oxidative metabolism and a very active glycolysis even in the presence of oxygen (Walburg effect). This leads a reduced synthesis of citrate which causes a decrease in acidity within the cells which favors glycolysis and tumor growth (4). In order to increase the citrate concentration we have treated HepG2 cells with different concentration of sodium citrate. The results obtained show that the citrate promote a metabolic reprogamming that modify the citrate lyase expression and histone acetylation. 1. Philippe Icard, Laurent Poulain, Hubert Lincet (2011). Understanding the central role of citrate in the metabolism of cancer cells. Biochimica et Biophysica Acta 1825 111-116. 2. Bauer DE1, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005). ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24(41):6314-22. 3. Ralph J. DeBerardinis and Navdeep S. Chandel (2016). Fundamentals of cancer metabolism. Oncology, 2:e1600200. 4. Steven J. Bensinger and Heather R. Christofk (2012). New aspects of the Warburg effect in cancer cell biology. Seminars in Cell  Developmental Biology 23 352-361. FUNDED BY INBIOMED PROJECT (MIUR, ARS01_01081)