title: UTX inhibits EMT-induced breast CSC properties by epigenetic repression of EMT genes in cooperation with LSD1 and HDAC1.
abstract: The histone H3K27 demethylase, UTX, is a known component of the H3K4 methyltransferase MLL complex, but its functional association with H3K4 methylation in human cancers remains largely unknown. Here we demonstrate that UTX loss induces epithelial-mesenchymal transition (EMT)-mediated breast cancer stem cell (CSC) properties by increasing the expression of the SNAIL, ZEB1 and ZEB2 EMT transcription factors (EMT-TFs) and of the transcriptional repressor CDH1. UTX facilitates the epigenetic silencing of EMT-TFs by inducing competition between MLL4 and the H3K4 demethylase LSD1. EMT-TF promoters are occupied by c-Myc and MLL4, and UTX recognizes these proteins, interrupting their transcriptional activation function. UTX decreases H3K4me2 and H3 acetylation at these promoters by forming a transcriptional repressive complex with LSD1, HDAC1 and DNMT1. Taken together, our findings indicate that UTX is a prominent tumour suppressor that functions as a negative regulator of EMT-induced CSC-like properties by epigenetically repressing EMT-TFs.
authors: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors: Hee-Joo
authors: HJ
authors: Choi
authors: Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea.
authors: Ji-Hye
authors: JH
authors: Park
authors: College of Pharmacy, Dongguk University, Seoul, Korea.
authors: Mikyung
authors: M
authors: Park
authors: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors: Hee-Young
authors: HY
authors: Won
authors: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors: Hyeong-Seok
authors: HS
authors: Joo
authors: College of Pharmacy, Dongguk University, Seoul, Korea.
authors: Chang Hoon
authors: CH
authors: Lee
authors: Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea jy2jy2@hanyang.ac.kr gkong@hanyang.ac.kr.
authors: Jeong-Yeon
authors: JY
authors: Lee
authors: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea jy2jy2@hanyang.ac.kr gkong@hanyang.ac.kr.
authors: Gu
authors: G
authors: Kong
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D063185:Epigenetic Repression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000502:physiology; D056466:Histone Demethylases / Q000235:genetics* / Q000502:physiology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; C523998:KDM6A protein, human; C495195:KDM1A protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: EMT; UTX; breast CSC