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.
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References
Visvader JE, Lindeman GJ . Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755–768.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.
O'Brien CA, Pollett A, Gallinger S, Dick JE . A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008; 15: 504–514.
Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006; 25: 1696–1708.
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ . Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005; 65: 10946–10951.
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66: 9339–9344.
Xin L, Lukacs RU, Lawson DA, Cheng D, Witte ON . Self-renewal and multilineage differentiation in vitro from murine prostate stem cells. Stem Cells 2007; 25: 2760–2769.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797–1806.
Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K et al. Cancer stem cell markers in common cancers - therapeutic implications. Trends Mol Med 2008; 14: 450–460.
Dote H, Toyooka S, Tsukuda K, Yano M, Ouchida M, Doihara H et al. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin Cancer Res 2004; 10: 2082–2089.
Yano M, Toyooka S, Tsukuda K, Dote H, Ouchida M, Hanabata T et al. Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers. Int J Cancer 2005; 113: 59–66.
Dote H, Toyooka S, Tsukuda K, Yano M, Ota T, Murakami M et al. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour. Br J Cancer 2005; 92: 1117–1125.
Xie D, Gore C, Liu J, Pong RC, Mason R, Hao G et al. Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proc Natl Acad Sci USA 2010; 107: 2485–2490.
Xie D, Gore C, Zhou J, Pong RC, Zhang H, Yu L et al. DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc Natl Acad Sci USA 2009; 106: 19878–19883.
Kyprianou N . ASK-ing EMT not to spread cancer. Proc Natl Acad Sci USA 2010; 107: 2731–2732.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.
Polyak K, Weinberg RA . Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–273.
Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009; 11: 1487–1495.
Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE 2010; 5: e12445.
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 1990; 63: 213–224.
Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17: 211–215.
Wang Z, Tseng CP, Pong RC, Chen H, McConnell JD, Navone N et al. The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2. J Biol Chem 2002; 277: 12622–12631.
Yamamoto K, Tojo A, Aoki N, Shibuya M . Characterization of the promoter region of the human c-kit proto-oncogene. Jpn J Cancer Res 1993; 84: 1136–1144.
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M . Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J 1998; 17: 4358–4369.
Munugalavadla V, Dore LC, Tan BL, Hong L, Vishnu M, Weiss MJ et al. Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. Mol Cell Biol 2005; 25: 6747–6759.
Sundstrom M, Vliagoftis H, Karlberg P, Butterfield JH, Nilsson K, Metcalfe DD et al. Functional and phenotypic studies of two variants of a human mast cell line with a distinct set of mutations in the c-kit proto-oncogene. Immunology 2003; 108: 89–97.
Feng LX, Ravindranath N, Dym M . Stem cell factor/c-kit up-regulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia. J Biol Chem 2000; 275: 25572–25576.
Yoshinaga K, Nishikawa S, Ogawa M, Hayashi S, Kunisada T, Fujimoto T . Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function. Development 1991; 113: 689–699.
Efeyan A, Sabatini DM . mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 2009; 22: 169–176.
Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22: 7004–7014.
van der Poel HG . Mammalian target of rapamycin and 3-phosphatidylinositol 3-kinase pathway inhibition enhances growth inhibition of transforming growth factor-beta1 in prostate cancer cells. J Urol 2004; 172: 1333–1337.
Joensuu H, Dimitrijevic S . Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. Ann Med 2001; 33: 451–455.
Hua S, Kittler R, White KP . Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 2009; 137: 1259–1271.
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol 2008; 9: R137.
Strobl H, Takimoto M, Majdic O, Hocker P, Knapp W . Antigenic analysis of human haemopoietic progenitor cells expressing the growth factor receptor c-kit. Br J Haematol 1992; 82: 287–294.
Leong KG, Wang BE, Johnson L, Gao WQ . Generation of a prostate from a single adult stem cell. Nature 2008; 456: 804–808.
Zhang H, He Y, Dai S, Xu Z, Luo Y, Wan T et al. AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. J Clin Invest 2008; 118: 3904–3916.
Wu K, Liu J, Tseng SF, Gore C, Ning Z, Sharifi N et al. The role of DAB2IP in androgen receptor activation during prostate cancer progression. Oncogene 2013; 33: 1954–1963.
Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29.
Wright JL, Dalkin BL, True LD, Ellis WJ, Stanford JL, Lange PH et al. Positive surgical margins at radical prostatectomy predict prostate cancer specific mortality. J Urol 2010; 183: 2213–2218.
Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ . Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 2005; 5: 899–904.
Hassan HT, Zander A . Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta Haematol 1996; 95: 257–262.
Chambeyron S, Bickmore WA . Does looping and clustering in the nucleus regulate gene expression? Curr Opin Cell Biol 2004; 16: 256–262.
Chen H, Karam JA, Schultz R, Zhang Z, Duncan C, Hsieh JT . Cloning of mouse Dab2ip gene, a novel member of the RasGTPase-activating protein family and characterization of its regulatory region in prostate. DNA Cell Biol 2006; 25: 232–245.
Li J, Quirt J, Do HQ, Lyte K, Fellows F, Goodyer CG et al. Expression of c-Kit receptor tyrosine kinase and effect on beta-cell development in the human fetal pancreas. Am J Physiol Endocrinol Metab 2007; 293: E475–E483.
Ma F, Chen F, Chi Y, Yang S, Lu S, Han Z . Isolation of pancreatic progenitor cells with the surface marker of hematopoietic stem cells. Int J Endocrinol 2012; 2012: 948683.
Rangel EB, Gomes SA, Dulce RA, Premer C, Rodrigues CO, Kanashiro-Takeuchi RM et al. C-Kit Cells Isolated from Developing Kidneys are a Novel Population of Stem Cells with Regenerative Potential. Stem Cells 2013; 31: 1644–1656.
Gleason DF . Histologic grading of prostate cancer: a perspective. Hum Pathol 1992; 23: 273–279.
Nagle RB, Ahmann FR, McDaniel KM, Paquin ML, Clark VA, Celniker A . Cytokeratin characterization of human prostatic carcinoma and its derived cell lines. Cancer Res 1987; 47: 281–286.
Burger PE, Xiong X, Coetzee S, Salm SN, Moscatelli D, Goto K et al. Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc Natl Acad Sci USA 2005; 102: 7180–7185.
Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON . Identification of a cell of origin for human prostate cancer. Science 2010; 329: 568–571.
Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007; 26: 6979–6988.
Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001; 7: 1028–1034.
Kong Z, Raghavan P, Xie D, Boike T, Burma S, Chen D et al. Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells. Int J Radiat Oncol Biol Phys 2010; 78: 1210–1218.
Wu K, Xie D, Zou Y, Zhang T, Pong RC, Xiao G et al. The mechanism of DAB2IP in chemo-resistance of prostate cancer cells. Clin Cancer Res 2013; 19: 4740–4749.
Kong Z, Xie D, Boike T, Raghavan P, Burma S, Chen DJ et al. Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. Cancer Res 2010; 70: 2829–2839.
Yu M, Smolen GA, Zhang J, Wittner B, Schott BJ, Brachtel E et al. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev 2009; 23: 1737–1742.
Lawson DA, Xin L, Lukacs RU, Cheng D, Witte ON . Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci USA 2007; 104: 181–186.
Kim M, Turnquist H, Jackson J, Sgagias M, Yan Y, Gong M et al. The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 2002; 8: 22–28.
Acknowledgements
We thank Mrs Mary Barnes for editing this manuscript. This work was supported in part by grants from the United States Army (W81XWH-11-1-0491 to J-TH) and National Institutes of Health (CA182670 to J-TH).
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Yun, EJ., Baek, S., Xie, D. et al. DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1. Oncogene 34, 2741–2752 (2015). https://doi.org/10.1038/onc.2014.215
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DOI: https://doi.org/10.1038/onc.2014.215
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