title: Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.
abstract: Inactivation of the tumor suppressor Ras-association domain family 1 isoform A (RASSF1A) due to epigenetic silencing occurs in a variety of human cancers, and still largely unknown are the regulators and mechanisms underlying RASSF1A gene promoter methylation. Herein, we report that this methylation is regulated by p53 and death-associated protein 6 (DAXX) in acute lymphoblastic leukemia (ALL). We found that p53 bound to the RASSF1A promoter, recruiting DAXX as well as DNA methyltransferase 1 (DNMT1) for DNA methylation, which subsequently resulted in inactivation of RASSF1A in wild-type p53 ALL cells. Although the presence of p53 was required for the recruitment of DAXX and DNMT1 to the RASSF1A promoter, fluctuation in p53 protein levels did not affect the rates of RASSF1A methylation. Conversely, methylation of RASSF1A promoter was critically controlled by DAXX, as the enforced overexpression of DAXX led to enhanced RASSF1A promoter methylation, whereas inhibition of DAXX reduced RASSF1A methylation. Interestingly, we found that the p53/DAXX-mediated RASSF1A methylation regulated murine double minute 2 (MDM2) protein stability in ALL. Our results reveal a novel function for p53 in the methylation of RASSF1A promoter by its interaction with DAXX. Discovery of this mechanism provides new insight into the interactions among the tumor-related factors p53, RASSF1A, DAXX, and MDM2 in cancer pathogenesis.
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Jiansha
authors.initials: J
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Tian
authors.forename: Lubing
authors.initials: L
authors.lastname: Gu
authors.forename: Muxiang
authors.initials: M
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004247:DNA; D019175:DNA Methylation; D017931:DNA Primers; D006801:Humans; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D017931:DNA Primers; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA