title: DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1.
abstract: Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Baek
authors.affiliation: Department of General Surgery, Tongji Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S-F
authors.initials: SF
authors.lastname: Tseng
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Dobin
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hernandez
authors.affiliation: 1] Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1] Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: D
authors.initials: D
authors.lastname: He
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Eugene McDermott Center for Human Growth, University of Texas Southwestern Medical Center, Dallas, TX, USA [3] Development, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kittler
authors.affiliation: 1] Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung, Taiwan, Republic of China.
authors.forename: J-T
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D018398:Homeodomain Proteins; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020703:ras GTPase-Activating Proteins; C462952:DAB2IP protein, human; C486307:ZEB1 protein, human; C546842:MTOR protein, human