DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1

• Published in: Oncogene 2015-05, Vol.34 (21), p.2741-2752
• Main Authors: Yun, E-J, Baek, S T, Xie, D, Tseng, S-F, Dobin, T, Hernandez, E, Zhou, J, Zhang, L, Yang, J, Sun, H, Xiao, G, He, D, Kittler, R, Hsieh, J-T
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/395; 631/67/71; 631/80/86; AKT protein; Analysis; Animals; Apoptosis; c-Kit protein; c-Myc protein; Cancer; Care and treatment; Cell Biology; Cell Line, Tumor; Cell proliferation; Diagnosis; Drug resistance; Evidence-based medicine; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Gene silencing; Genotype & phenotype; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; Health aspects; Homeodomain Proteins - metabolism; Human Genetics; Humans; Internal Medicine; KIT protein; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Mice, SCID; Myc protein; Neoplasm Recurrence, Local - metabolism; Neoplastic Stem Cells - metabolism; Oncology; original-article; Phenotype; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Prostate; Prostate cancer; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-kit - metabolism; Proto-Oncogene Proteins c-myc - metabolism; ras GTPase-Activating Proteins - metabolism; Regulatory sequences; Signal transduction; Signal Transduction - physiology; Stem cell factor; Stem cells; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - metabolism; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.215

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.