title: Impairment of DYRK2 augments stem-like traits by promoting KLF4 expression in breast cancer.
abstract: Whereas accumulating studies have supported the cancer stem cell theory, a specific therapy targeting a cancer stem cell subpopulation has not been established. Here, we show that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells. Downregulation of DYRK2 promotes cancer stem-like traits in vitro, tumourigenesis in vivo and the proportion of the cancer stem cell population in human breast cancer tissues. We found that Krupple-like factor 4 (KLF4) serves as a key mediator of DYRK2's control over the cancer stem phenotype. Reduced DYRK2 expression increases KLF4 expression, which induces cancer stem-like properties. We identified androgen receptor (AR) as a transcription factor binding to the KLF4 promoter region; this process is dependent on DYRK2 kinase activity. Our findings delineate a mechanism of cancer stem cell regulation by the DYRK2-AR-KLF4 axis in breast cancer. Targeting of this pathway may be a promising strategy against breast cancer stem cells.
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.|Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Mimoto
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.|Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Imawari
authors.affiliation: Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hirooka
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takeyama
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015533:Transcriptional Activation; D000097603:Dyrk Kinases
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011944:Receptors, Androgen; D000097603:Dyrk Kinases; C000715467:KLF4 protein, human