title: Chemo-Genetic Interactions Between Histone Modification and the Antiproliferation Drug AICAR Are Conserved in Yeast and Humans.
abstract: Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via the combined effects of both the drug and mutations on G1 cyclins. Our results point to AICAR impacting on Cln3 subcellular localization and at the Cln1 protein level, while the bre1 or set1 deletion affected CLN1 and CLN2 expression. As a consequence, AICAR and bre1/set1 deletions jointly affected all three G1 cyclins (Cln1, Cln2, and Cln3), leading to a condition known to result in synthetic lethality. Significantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Indeed, knock-down of RNF40, ASH2L, and KMT2D/MLL2 induced a highly significant increase in AICAR sensitivity. Given that KMT2D/MLL2 is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ceschin
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Jim
authors.initials: J
authors.lastname: Dompierre
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Gueniot
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Pinson
authors.affiliation: Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France b.daignan-fornier@ibgc.cnrs.fr.|Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Daignan-Fornier
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000970:Antineoplastic Agents; C472168:Bre1 protein, S cerevisiae; C082719:CLN1 protein, S cerevisiae; D016213:Cyclins; D004268:DNA-Binding Proteins; D006657:Histones; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D012265:Ribonucleotides; D029701:Saccharomyces cerevisiae Proteins; D000091346:Tripeptidyl-Peptidase 1; D000620:Aminoimidazole Carboxamide; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae; C031143:AICA ribonucleotide
keywords: Synthetic lethality; cancer cells; cell cycle; histone modification; yeast