Requirement of RIZ1 for cancer prevention by methyl-balanced diet

• Published in: PloS one Vol. 3; no. 10; p. e3390
• Main Authors: Zhou, Wenyun, Alonso, Sergio, Takai, Daisaku, Lu, Shelly C, Yamamoto, Fumiichiro, Perucho, Manuel, Huang, Shi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.10.2008; Public Library of Science (PLoS)
• Subjects: Adenosylmethionine; Adenoviruses; Amino acids; Animals; c-Jun protein; Cancer; Cancer prevention; Carcinogenesis; Carcinogens; Chromatin; Comparative analysis; Deoxyribonucleic acid; Diet; Disease prevention; DNA; DNA methylation; DNA microarrays; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Enzymes; Food; Gastroenterology and Hepatology/Gastrointestinal Cancers; Gene expression; Gene Expression Regulation; Gene silencing; Genes; Genomes; Health aspects; Histone H3; Histone-Lysine N-Methyltransferase; Liver; Liver cancer; Liver diseases; Lymphoma; Lysine; Medical research; Metabolites; Methionine - administration & dosage; Methylation; Methyltransferases; Mice; Mice, Knockout; Neoplasms - prevention & control; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Nutrients; Nutrition/Malnutrition; Oncology; Prevention; Proteins; Rodentia; Rodents; S-Adenosylmethionine; Senescence; Transcription factors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - physiology; Tumor suppressor genes; Tumors; Vitamin B; La Jolla California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003390

The typical Western diet is not balanced in methyl nutrients that regulate the level of the methyl donor S-adenosylmethionine (SAM) and its derivative metabolite S-adenosylhomocysteine (SAH), which in turn may control the activity of certain methyltransferases. Feeding rodents with amino acid defined and methyl-imbalanced diet decreases hepatic SAM and causes liver cancers. RIZ1 (PRDM2 or KMT8) is a tumor suppressor and functions in transcriptional repression by methylating histone H3 lysine 9. Here we show that a methyl-balanced diet conferred additional survival benefits compared to a tumor-inducing methyl-imbalanced diet only in mice with wild type RIZ1 but not in mice deficient in RIZ1. While absence of RIZ1 was tumorigenic in mice fed the balanced diet, its presence did not prevent tumor formation in mice fed the imbalanced diet. Microarray and gene expression analysis showed that, unlike most of its related enzymes, RIZ1 was upregulated by methyl-balanced diet. Methyl-balanced diet did not fully repress oncogenes such as c-Jun in the absence of RIZ1. Higher RIZ1 activity was associated with greater H3 lysine 9 methylation in RIZ1 target genes as shown by chromatin immunoprecipitation analysis. The data identify RIZ1 as a critical target of methyl-balanced diet in cancer prevention. The molecular understanding of dietary carcinogenesis may help people make informed choices on diet, which may greatly reduce the incidence of cancer.