title: KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties.
abstract: Studies have reported that interactions between keratins (KRTs) and other proteins initiate signaling cascades that regulate cell migration, invasion, and metastasis. In the current study, we found that expression of KRT19 was specifically high in breast cancers and significantly correlated with their invasiveness. Moreover, knockdown of KRT19 led to increased proliferation, migration, invasion, drug resistance, and sphere formation in breast cancer cells via an upregulated NOTCH signaling pathway. This was owing to reduced expression of NUMB, an inhibitory protein of the NOTCH signaling pathway. In addition, we found that KRT19 interacts with β-catenin/RAC1 complex and enhances the nuclear translocation of β-catenin. Concordantly, knockdown of KRT19 suppressed the nuclear translocation of β-catenin as well as β-catenin-mediated NUMB expression. Furthermore, modulation of KRT19-mediated regulation of NUMB and NOTCH1 expression led to the repression of the cancer stem cell properties of breast cancer patient-derived CD133high/CXCR4high/ALDH1highcancer stem-like cells (CSLCs), which showed very low KRT19 and high NOTCH1 expression. Taken together, our study suggests a novel function for KRT19 in the regulation of nuclear import of the β-catenin/RAC1 complex, thus modulating the NUMB-dependent NOTCH signaling pathway in breast cancers and CSLCs, which might bear potential clinical implications for cancer or CSLC treatment.
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: S K
authors.initials: SK
authors.lastname: Saha
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: H Y
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: B W
authors.initials: BW
authors.lastname: Kim
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: A A
authors.initials: AA
authors.lastname: Dayem
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: G-M
authors.initials: GM
authors.lastname: Yang
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: Y F
authors.initials: YF
authors.lastname: Yin
authors.affiliation: Department of Animal Biotechnology, Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea.
authors.forename: S-G
authors.initials: SG
authors.lastname: Cho
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D053539:Keratin-19; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C107953:RAC1 protein, human; D051880:Receptors, Notch; D051176:beta Catenin; D020830:rac1 GTP-Binding Protein