MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition.
The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Huacheng
H
Luo
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Anitha K
AK
Shenoy
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Xuehui
X
Li
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Yue
Y
Jin
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Lihua
L
Jin
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Qingsong
Q
Cai
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Ming
M
Tang
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Yang
Y
Liu
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Hao
H
Chen
Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
David
D
Reisman
Department of Molecular Genetics and Microbiology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Lizi
L
Wu
Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Edward
E
Seto
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Yi
Y
Qiu
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Yali
Y
Dou
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Robert A
RA
Casero
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: jrlu@ufl.edu.
Jianrong
J
Lu
D000107:Acetylation; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009707:Nucleosomes / Q000378:metabolism
D015820:Cadherins; D006657:Histones; D046912:Multiprotein Complexes; D009707:Nucleosomes; D056466:Histone Demethylases; C495195:KDM1A protein, human; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; D008239:Lysine