Morales-Ruiz, TeresaGarcia-Ortiz, Maria VictoriaDevesa-Guerra, IvanRaya-Ruiz, LauraTejedor, Juan RBayon, Gustavo FSierra, Marta IFraga, Mario FAriza, Rafael RRoldan-Arjona, Teresa2023-01-252023-01-252018-02-07Morales-Ruiz T, García-Ortiz MV, Devesa-Guerra I, Raya-Ruiz L, Tejedor JR, Bayón GF, et al. DNA methylation reprogramming of human cancer cells by expression of a plant 5-methylcytosine DNA glycosylase. Epigenetics. 2018;13(1):95-107http://hdl.handle.net/10668/11902Patterns 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.enDNA demethylationDNA methylationEpigeneticsBase excision repairColon cancerAnimalsAntineoplastic agentsArabidopsis proteinsCell cycleCell line, tumorColonic neoplasmsDNA methylationDNA repairFluorouracilGene expression regulation, neoplasticGenes, tumor suppressorGenes, p16HumansMice, nudeN-glycosyl hydrolasesOncogene proteinsOxaliplatinReceptor tyrosine kinase-like orphan receptorsTrans-activatorsTransgenesXenograft model antitumor assaysresearch article29235922open accessAntineoplásicosCiclo celularGenes supresores de tumorLínea celular tumoralMetilación de ADNNeoplasias del colonRegulación neoplásica de la expresión génicaReparación del ADN10.1080/15592294.2017.14141281559-2308PMC5836972https://www.tandfonline.com/doi/pdf/10.1080/15592294.2017.1414128?needAccess=truehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836972/pdf