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PLOS Biology  2009 

Atonal homolog 1 Is a Tumor Suppressor Gene

DOI: 10.1371/journal.pbio.1000039

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Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.


[1]  Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong D, et al. (2000) Functional conservation of atonal and Math1 in the CNS and PNS. Development 127: 1039–1048.
[2]  Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294: 2155–2158.
[3]  Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, et al. (2007) Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132: 2478–2488.
[4]  Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, et al. (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390: 169–172.
[5]  Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, et al. (1999) Math1: an essential gene for the generation of inner ear hair cells. Science 284: 1837–1841.
[6]  Wang VY, Hassan BA, Bellen HJ, Zoghbi HY (2002) Drosophila atonal fully rescues the phenotype of Math1 null mice: new functions evolve in new cellular contexts. Curr Biol 12: 1611–1616.
[7]  Bossuyt W, De Geest N, Aerts S, Leenaerts I, Marynen P, et al. (2009) The Atonal proneural transcription factor links differentiation and tumor formation in Drosophila. PLoS Biol 7: e1000040. doi:10.1371/journal.pbio.1000040.
[8]  Brenner B, Sulkes A, Rakowsky E, Feinmesser M, Yukelson A, et al. (2001) Second neoplasms in patients with Merkel cell carcinoma. Cancer 91: 1358–1362.
[9]  O'Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96: 1420–1425.
[10]  Leow CC, Romero MS, Ross S, Polakis P, Gao WQ (2004) Hath1, down-regulated in colon adenocarcinomas, inhibits proliferation and tumorigenesis of colon cancer cells. Cancer Res 64: 6050–6057.
[11]  Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307: 1904–1909.
[12]  Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, et al. (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256: 668–670.
[13]  Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247: 322–324.
[14]  Colnot S, Niwa-Kawakita M, Hamard G, Godard C, Le Plenier S, et al. (2004) Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest 84: 1619–1630.
[15]  Niwa N, Hiromi Y, Okabe M (2004) A conserved developmental program for sensory organ formation in Drosophila melanogaster. Nat Genet 36: 293–297.
[16]  Leonard JH, Cook AL, Van Gele M, Boyle GM, Inglis KJ, et al. (2002) Proneural and proneuroendocrine transcription factor expression in cutaneous mechanoreceptor (Merkel) cells and Merkel cell carcinoma. Int J Cancer 101: 103–110.
[17]  Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, et al. (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36: 361–374.
[18]  Sun Y, Jan LY, Jan YN (1998) Transcriptional regulation of atonal during development of the Drosophila peripheral nervous system. Development 125: 3731–3740.
[19]  Helms AW, Abney AL, Ben-Arie N, Zoghbi HY, Johnson JE (2000) Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development 127: 1185–1196.
[20]  Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, et al. (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439: 871–874.
[21]  Tong C, Yin Z, Song Z, Dockendorff A, Huang C, et al. (2007) c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. Am J Pathol 171: 297–303.
[22]  Chen N, Nomura M, She QB, Ma WY, Bode AM, et al. (2001) Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res 61: 3908–3912.
[23]  Leonard JH, Bell JR, Kearsley JH (1993) Characterization of cell lines established from Merkel-cell ("small-cell") carcinoma of the skin. Int J Cancer 55: 803–810.
[24]  Leonard JH, Dash P, Holland P, Kearsley JH, Bell JR (1995) Characterisation of four Merkel cell carcinoma adherent cell lines. Int J Cancer 60: 100–107.
[25]  Jarman AP, Grell EH, Ackerman L, Jan LY, Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369: 398–400.
[26]  John A, Smith ST, Jaynes JB (1995) Inserting the Ftz homeodomain into engrailed creates a dominant transcriptional repressor that specifically turns off Ftz target genes in vivo. Development 121: 1801–1813.
[27]  Ligoxygakis P, Yu SY, Delidakis C, Baker NE (1998) A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex. Development 125: 2893–2900.
[28]  Hassan BA, Bellen HJ (2000) Doing the MATH: is the mouse a good model for fly development? Genes Dev 14: 1852–1865.
[29]  Li Y, Baker NE (2001) Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye. Curr Biol 11: 330–338.
[30]  Kim JW, Kim MJ, Kim KJ, Yun HJ, Chae JS, et al. (2005) Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway. Proc Natl Acad Sci U S A 102: 14308–14313.
[31]  Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, et al. (2000) L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39: 8698–8704.
[32]  Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103: 211–225.
[33]  Fundin BT, Silos-Santiago I, Ernfors P, Fagan AM, Aldskogius H, et al. (1997) Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR. Dev Biol 190: 94–116.
[34]  Szeder V, Grim M, Kucera J, Sieber-Blum M (2003) Neurotrophin-3 signaling in mammalian Merkel cell development. Dev Dyn 228: 623–629.
[35]  Tapley P, Lamballe F, Barbacid M (1992) K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors. Oncogene 7: 371–381.
[36]  Nye SH, Squinto SP, Glass DJ, Stitt TN, Hantzopoulos P, et al. (1992) K-252a and staurosporine selectively block autophosphorylation of neurotrophin receptors and neurotrophin-mediated responses. Mol Biol Cell 3: 677–686.
[37]  Ruggeri BA, Miknyoczki SJ, Singh J, Hudkins RL (1999) Role of neurotrophin-trk interactions in oncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors in pre-clinical tumor models. Curr Med Chem 6: 845–857.
[38]  Shin M, Yan C, Boyd D (2002) An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. Biochim Biophys Acta 1589: 311–316.
[39]  Alani R, Brown P, Binétruy B, Dosaka H, Rosenberg RK, et al. (1991) The transactivating domain of the c-Jun proto-oncoprotein is required for cotransformation of rat embryo cells. Mol Cell Biol 11: 6286–6295.
[40]  Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, et al. (2008) GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13: 141–152.
[41]  Harris H (2004) Tumor suppression: putting on the brakes. Nature 427: 201.
[42]  Heasley LE, Han SY (2006) JNK regulation of oncogenesis. Mol Cells 21: 167–173.
[43]  Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, et al. (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278: 46107–46116.
[44]  van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, et al. (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963.
[45]  Kiesslich R, Goetz M, Angus EM, Hu Q, Guan Y, et al. (2007) Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology 133: 1769–1778.
[46]  Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, et al. (2003) Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 124: 762–777.
[47]  Flint N, Cove FL, Evans GS (1991) A low-temperature method for the isolation of small-intestinal epithelium along the crypt-villus axis. Biochem J 280(Pt 2): 331–334.
[48]  Taylor JA, Martin CA, Nair R, Guo J, Erwin CR, et al. (2008) Lessons learned: optimization of a murine small bowel resection model. J Pediatr Surg 43: 1018–1024.
[49]  Van Damme A, Thorrez L, Ma L, Vandenburgh H, Eyckmans J, et al. (2006) Efficient lentiviral transduction and improved engraftment of human bone marrow mesenchymal cells. Stem Cells 24: 896–907.
[50]  VandenDriessche T, Naldini L, Collen D, Chuah MK (2002) Oncoretroviral and lentiviral vector-mediated gene therapy. Methods Enzymol 346: 573–589.
[51]  VandenDriessche T, Thorrez L, Naldini L, Follenzi A, Moons L, et al. (2002) Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. Blood 100: 813–822.


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