title: DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression.
abstract: DOT1L has emerged as an anticancer target for MLL-associated leukaemias; however, its functional role in solid tumours is largely unknown. Here we identify that DOT1L cooperates with c-Myc and p300 acetyltransferase to epigenetically activate epithelial-mesenchymal transition (EMT) regulators in breast cancer progression. DOT1L recognizes SNAIL, ZEB1 and ZEB2 promoters via interacting with the c-Myc-p300 complex and facilitates lysine-79 methylation and acetylation towards histone H3, leading to the dissociation of HDAC1 and DNMT1 in the regions. The upregulation of these EMT regulators by the DOT1L-c-Myc-p300 complex enhances EMT-induced breast cancer stem cell (CSC)-like properties. Furthermore, in vivo orthotopic xenograft models show that DOT1L is required for malignant transformation of breast epithelial cells and breast tumour initiation and metastasis. Clinically, DOT1L expression is associated with poorer survival and aggressiveness of breast cancers. Collectively, we suggest that cooperative effect of DOT1L and c-Myc-p300 is critical for acquisition of aggressive phenotype of breast cancer by promoting EMT/CSC.
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Min-Hyung
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul 133-791, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Hee-Joo
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Won
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Yeon-Ji
authors.initials: YJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon 405-840, Republic of Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Song
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Hyun Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors.forename: Young-Ha
authors.initials: YH
authors.lastname: Oh
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul 133-791, Korea.
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 1] Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Korea [2] Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul 133-791, Korea.
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018450:Disease Progression; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human