title: Histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis.
abstract: Histone demethylase PHF8 is upregulated and plays oncogenic roles in various cancers; however, the mechanisms underlying its dysregulation and functions in carcinogenesis remain obscure. Here, we report the novel functions of PHF8 in EMT (epithelial to mesenchymal transition) and breast cancer development. Genome-wide gene expression analysis revealed that PHF8 overexpression induces an EMT-like process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF-β signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC post-transcriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR-22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-β signaling. This novel MYC/microRNAs/PHF8 regulatory axis thus places PHF8 as an important downstream effector of MYC. Indeed, PHF8 contributes to MYC-induced cell proliferation and the expression of EMT-related genes. We also report that PHF8 plays important roles in breast cancer cell migration and tumor growth. These oncogenic functions of PHF8 in breast cancer confer its candidacy as a promising therapeutic target for this disease.
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Shao
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Peterson Kariuki
authors.initials: PK
authors.lastname: Maina
authors.affiliation: Department of Histology and Embryology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
authors.forename: Jiayue
authors.initials: J
authors.lastname: Cui
authors.affiliation: Iowa Institute of Human Genetics, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Bair
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA.
authors.forename: Tiandao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Shaikamjad
authors.initials: S
authors.lastname: Umesalma
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, IA 52242, USA.
authors.forename: Hank Heng
authors.initials: HH
authors.lastname: Qi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D006657:Histones; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D056466:Histone Demethylases; C511934:PHF8 protein, human