DNA methylation reprogramming of human cancer cells by expression of a plant 5-methylcytosine DNA glycosylase.

Abstract

Patterns of DNA methylation, an important epigenetic modification involved in gene silencing and development, are disrupted in cancer cells. Understanding the functional significance of aberrant methylation in tumors remains challenging, due in part to the lack of suitable tools to actively modify methylation patterns. DNA demethylation caused by mammalian DNA methyltransferase inhibitors is transient and replication-dependent, whereas that induced by TET enzymes involves oxidized 5mC derivatives that perform poorly understood regulatory functions. Unlike animals, plants possess enzymes that directly excise unoxidized 5mC from DNA, allowing restoration of unmethylated C through base excision repair. Here, we show that expression of Arabidopsis 5mC DNA glycosylase DEMETER (DME) in colon cancer cells demethylates and reactivates hypermethylated silenced loci. Interestingly, DME expression causes genome-wide changes that include both DNA methylation losses and gains, and partially restores the methylation pattern observed in normal tissue. Furthermore, such methylome reprogramming is accompanied by altered cell cycle responses and increased sensibility to anti-tumor drugs, decreased ability to form colonospheres, and tumor growth impairment in vivo. Our study shows that it is possible to reprogram a human cancer DNA methylome by expression of a plant DNA demethylase.

• Authors: Teresa Morales-Ruiz, María Victoria García-Ortiz, Iván Devesa-Guerra, Laura Raya-Ruiz, Juan R Tejedor, Gustavo F Bayón, Marta I Sierra, Mario F Fraga, Rafael R Ariza, Teresa Roldán-Arjona
• Journal: Epigenetics (Epigenetics) Vol. 13 Issue 1 Pg. 95-107 ( 2018) ISSN: 1559-2308 [Electronic] United States
• PMID: 29235922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arabidopsis Proteins
• CDK2AP2 protein, human
• Oncogene Proteins
• Trans-Activators
• Oxaliplatin
• ROR2 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• DEMETER protein, Arabidopsis
• N-Glycosyl Hydrolases
• Fluorouracil

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Arabidopsis Proteins (genetics, metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, pathology)
• DNA Methylation
• DNA Repair (genetics)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Genes, p16
• Humans
• Mice, Nude
• N-Glycosyl Hydrolases (genetics, metabolism)
• Oncogene Proteins (genetics)
• Oxaliplatin (pharmacology)
• Receptor Tyrosine Kinase-like Orphan Receptors (genetics)
• Trans-Activators (genetics, metabolism)
• Transgenes
• Xenograft Model Antitumor Assays