title: Identification and characterization of DNAzymes targeting DNA methyltransferase I for suppressing bladder cancer proliferation.
abstract: Epigenetic inactivation of genes plays a critical role in many important human diseases, especially in cancer. A core mechanism for epigenetic inactivation of the genes is methylation of CpG islands in genome DNA, which is catalyzed by DNA methyltransferases (DNMTs). The inhibition of DNMTs may lead to demethylation and expression of the silenced tumor suppressor genes. Although DNMT inhibitors are currently being developed as potential anticancer agents, only limited success is achieved due to substantial toxicity. Here, we utilized a multiplex selection system to generate efficient RNA-cleaving DNAzymes targeting DNMT1. The lead molecule from the selection was shown to possess efficient kinetic profiles and high efficiency in inhibiting the enzyme activity. Transfection of the DNAzyme caused significant down-regulation of DNMT1 expression and reactivation of p16 gene, resulting in reduced cell proliferation of bladder cancers. This study provides an alternative for targeting DNMTs for potential cancer therapy.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Nianhua
authors.initials: N
authors.lastname: Ding
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China. Electronic address: lunquansun@csu.edu.cn.
authors.forename: Lun-Quan
authors.initials: LQ
authors.lastname: Sun
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D021881:DNA, Catalytic / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D014162:Transfection; D001743:Urinary Bladder / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*
chemical_list: D021881:DNA, Catalytic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
keywords: Bladder cancer; DNAzyme; DNMTs; p16