Genome-wide analysis discloses reversal of the hypoxia-induced changes of gene expression in colon cancer cells by zinc supplementation

Michal Sheffer 1 , Amos J. Simon 2 , Jasmine Jacob-Hirsch 2 , Gideon Rechavi 2 , Eytan Domany 1 , David Givol 3 and Gabriella D’Orazi 4,5 1 Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel 2 Department of Pediatric Hematology-Oncology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel 4 Department of Experimental Oncology, Molecular Oncogenesis Laboratory, National Cancer Institute Regina Elena; Rome, Italy 5 Department of Oral Sciences, Nano and Biotechnology, University “G. d’Annunzio”, Chieti, Italy Received: December 20, 2011; Accepted: December 23, 2011; Published: December 24, 2011; Keywords: hypoxia, cobalt, pathway analysis, Principal Component Analysis (PCA), cDNA microarray, colon cancer Correspondence: David Givol, email: // Gabriella D’Orazi, email: // // Abstract Hypoxia-inducible factor 1 (HIF-1), the major transcription factor specifically activated during hypoxia, regulates genes involved in critical aspects of cancer biology, including angiogenesis, cell proliferation, glycolysis and invasion. The HIF-1a subunit is stabilized by low oxygen, genetic alteration and cobaltous ions, and its over-expression correlates with drug resistance and increased cancer mortality in various cancer types, therefore representing an important anticancer target. Zinc supplementation has been shown to counteract the hypoxic phenotype in cancer cells, in vitro and in vivo , hence, understanding the molecular pathways modulated by zinc under hypoxia may provide the basis for reprogramming signalling pathways for anticancer therapy. Here we performed genome-wide analyses of colon cancer cells treated with combinations of cobalt, zinc and anticancer drug and evaluated the effect of zinc on gene expression patterns. Using Principal Component Analysis we found that zinc markedly reverted the cobalt-induced changes of gene expression, with reactivation of the drug-induced transcription of pro-apoptotic genes. We conclude that the hypoxia pathway is a potential therapeutic target addressed by zinc that also influences tumor cell response to anticancer drug.