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Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

Oncogene volume 20, pages 24–33 (2001)Cite this article

Abstract

The hamster ornithine decarboxylase antizyme (ODC-Az) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial differentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a significant increase in demethylation of 5-methyl cytosines (m5C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development.

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References

  • Alani RM, Hasskarl J, Grace M, Hernandez MC, Israel MA and Munger K. . 1999 Proc. Natl. Acad. Sci. USA 96: 9637–9641.

  • Aringer M, Cheng A, Nelson JW, Chen M, Sudarshan C, Zhou YJ and O'Shea JJ. . 1999 Life Sci. 64: 2173–2186.

  • Auvinen M, Paasinen A, Andersson LC and Hölttä E. . 1992 Nature 360: 355–358.

  • Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK, Baylin SB and Graff JR. . 1999 Cancer Res. 59: 798–802.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP. . 1998 Adv. Cancer Res. 72: 141–196.

  • Baylin SB, Makos M, Wu JJ, Yen RW, de Bustros A, Vertino P and Nelkin BD. . 1991 Cancer Cells 3: 383–390.

  • Belinsky SA, Nikula KJ, Baylin SB and Issa JP. . 1996 Proc. Natl. Acad. Sci. USA 93: 4045–4050.

  • Bestor TH, Hellewell SB and Ingram VM. . 1984 Mol. Cell. Biol. 4: 1800–1806.

  • Bruey J-M, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, Gurbuxani S, Arrigo A-P, Kroemer G, Solary E and Garrido C. . 2000 Nature Cell Biol. 2: 645–652.

  • Chao C, Lotz MM, Clarke AC and Merucurio AM. . 1996 Cancer Res. 56: 4811–4819.

  • Chuang LS, Ian HI, Koh TW, Ng HH, Xu G and Li BF. . 1997 Science 277: 1996–2000.

  • Clifford A, Morgan D, Yuspa SH, Soler AP and Gilmour S. . 1995 Cancer Res. 55: 1680–1686.

  • Domann FE, Rice JC, Hendrix MJ and Futscher BW. . 2000 Int. J. Cancer 85: 805–810.

  • Duranton B, Keith G, Goss F, Bergmann C, Schleiffer R and Raul F. . 1998 Exp. Cell Res. 243: 319–325.

  • el-Deiry WS, Nelkin BD, Celano P, Yen RW, Falco JP, Hamilton SR and Baylin SB. . 1991 Proc. Natl. Acad. Sci. USA 88: 3470–3474.

  • Feuerstein BG, Williams LD, Basu HS and Marton LJ. . 1991 J. Cell Biochem. 46: 37–47.

  • Freshney RI. . 1994 Culture of Animal Cells: A Manuel of Basic Technique 3rd edn. Wiley-Liss: New York.

    Google Scholar 

  • Frostesjo L, Holm I, Grahn B, Page AW, Bestor TH and Heby O. . 1997 J. Biol. Chem. 272: 4359–4366.

  • Gaines DW, Friedman L and McCann PP. . 1988 Anal. Biochem. 174: 88–96.

  • Gimenez-Conti IB and Slaga TJ. . 1992 Adv. Exp. Med. Biol. 320: 63–67.

  • Gimenez-Conti IB and Slaga TJ. . 1993 J. Cell Biochem. (Suppl.) 83–90.

  • Gosule LC and Schellman JA. . 1978 J. Mol. Biol. 121: 311–326.

  • Harper JW. . 1997 Cancer Surv. 29: 91–107.

  • Hawtrey AO and Ariatti M. . 1984 Med. Hypotheses 15: 125–134.

  • Hayashi S and Canellakis ES. . 1989 Ornithine Decarboxylase: Biology, Enzymology, and Molecular Genetics Hayashi S. (ed.). Pergamon Press: New York pp. 47–58.

    Google Scholar 

  • Hayashi S, Murakami Y and Matsufuji S. . 1996 Trends Biochem. Sci. 21: 27–30.

  • Heby O, Persson L and Smith SS. . 1988 Adv. Exp. Med. Biol. 250: 291–299.

  • Heby O. . 1995 Int. J. Dev. Biol. 39: 737–757.

  • Henkel AW and Sankaranarayanan S. . 1999 Cell Tissue Res. 296: 229–233.

  • Hickok NJ and Uitto J. . 1992 J. Invest. Dermatol. 98: 327–332.

  • Iismaa TP and Shine J. . 1999 Results Probl. Cell Differ. 26: 257–291.

  • Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD, Hamilton SR and Baylin SB. . 1993 J. Natl. Cancer Inst. 85: 1235–1240.

  • Ito T, Noguchi Y, Udaka N, Kitamura H and Satoh S. . 1999 Histol Histopathol 14: 895–904.

  • Iwata S, Sato Y, Asada M, Takagi M, Tsujimoto A, Inaba T, Yamada T, Sakamoto S, Yata J, Shimogori T, Igarashi K and Mizutani S. . 1999 Oncogene 18: 165–172.

  • Janssen BL, van de Locht LT, Fourkour A, de Smet C, Mensink EJ, van Muijen GN and de Vries TJ. . 1999 Melanoma Res. 9: 213–222.

  • Kim H, Pennie WD, Sun Y and Colburn NH. . 1997a Biochem J. 324: 547–553.

  • Kim SY, Bachman NJ, Nair TS, Goldsmith S, Liebert M, Grossman HB, Lomax MI and Carey TE. . 1997b Cancer Res. 57: 38–42.

  • Laemmli UK. . 1970 Nature 227: 680–685.

  • Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA and Jaenisch R. . 1995 Cell 81: 197–205.

  • Li E, Bestor TH and Jaenisch R. . 1992 Cell 69: 915–926.

  • Li X and Coffino P. . 1994 Mol. Cell Biol. 14: 87–92.

  • Linden M, Anehus S, Langstrom E, Baldetorp B and Heby O. . 1985 J. Cell Physiol. 125: 273–276.

  • Lundell L and Rosengren E. . 1986 Scand. J. Gastroenterol. 21: 829–832.

  • Makos M, Nelkin BD, Lerman MI, Latif F, Zbar B and Baylin SB. . 1992 Proc. Natl. Acad. Sci. USA 89: 1929–1933.

  • Mao Y, Gurr JA and Hickok NJ. . 1993 Biochem J. 295: 641–644.

  • Marton LJ and Pegg AE. . 1995 Annu. Rev. Pharmacol. Toxicol. 35: 55–91.

  • Matsufuji S, Matsufuji T, Miyazaki Y, Atkins JF, Gesteland RF and Hayashi S-I. . 1995 Cell 80: 51–60.

  • McCarty ME. . 1997 Med. Hypotheses 48: 297–308.

  • Megosh L, Gilmour SK, Rosson D, Soler AP, Blessing M, Sawicki JA and O'Brien TG. . 1995 Cancer Res. 55: 4205–4209.

  • Mehlen P, Mehlen A, Godet J and Arrigo AP. . 1997 J. Biol. Chem. 272: 31657–31665.

  • Missero C, Di Cunto F, Kiyokawa H, Koff A and Dotto GP. . 1996 Genes Dev. 10: 3065–3075.

  • Mitchell JL, Choe CY, Judd GG, Daghfal DK, Kurzeja RJ and Leyser A. . 1996 Biochem. J. 317: 811–816.

  • Monzon RI, LaPres JJ and Hudson LG. . 1996 Cell Growth Differ. 7: 1751–1759.

  • Odukoya O, Schwartz J, Weichselbaum R and Shklar G. . 1983 J. Natl. Can. Inst. 71: 1252–1264.

  • Pawelczyk T and Lowenstein JM. . 1993 Biochem. Pharmacol. 45: 493–497.

  • Pegg AE. . 1986 Biochem. J. 234: 249–262.

  • Pegg AE, McGovern KA and Wiest L. . 1987 Biochem. J. 241: 305–307.

  • Pennie WD, Hegamyer GA, Young MR and Coluburn NH. . 1999 Cell Growth Differ. 10: 279–286.

  • Radford DM, Nakai H, Eddy RL, Haley LL, Byers MG, Henry WM, Lawrence DD, Porter CL and Shows TB. . 1990 Cancer Res. 50: 6146–6153.

  • Rideout WM, 3rd, Eversole-Cire P, Spruck CH, 3rd, Hustad CM, Coetzee GA, Gonzales FA and Jones PA. . 1994 Mol. Cell Biol. 14: 6143–6152.

  • Rofstad EK. . 2000 Int. J. Radiat Biol. 76: 589–605.

  • Romano M, Santacroce M, Bonelli P, Cecco L and Cerra M. . 1986 Int. J. Biol. Markers 2: 77–80.

  • Salzberg A, Golden K, Bodmer R and Bellen HJ. . 1996 Genetics 144: 183–196.

  • Sapienza C. . 1991 Biochim Biophys Acta. 1072: 51–61.

  • Sark MWJ, Fischer DF, de Meijer E, van de Putte P and Backendorf C. . 1998 J. Biol. Chem. 273: 24683–24692.

  • Seiler N and Knodgen B. . 1985 J. Chromatogr 339: 45–57.

  • Shin DM, Gimenez IB, Lee JS, Nishioka K, Wargovich MJ, Thacher S, Lotan R, Slaga TJ and Hong WK. . 1990 Cancer Res. 50: 2505–2510.

  • Sun Y, Hegamyer G, Kim H, Sithanandam K, Li H, Watts R and Colburn NH. . 1995 J. Biol. Chem. 270: 19312–19319.

  • Suzuki Takaoka A, Yamada T, Gotoh M, Kanai Y, Imai K and Hirohashi S. . 1998 J. Biol. Chem. 273: 33848–33855.

  • Tabor CW and Tabor H. . 1984 Annu Rev. Biochem 53: 747–790.

  • Takigawa M, Verma AK, Simsiman RC and Boutwell RK. . 1983 Cancer Res. 43: 3732–3738.

  • Tamori A, Nishiguchi S, Kuroki T, Seki S, Kobayashi K, Kinoshita H and Otani S. . 1994 Hepatology 20: 1179–1186.

  • Tomayko MM and Reynolds CP. . 1989 Cancer Chemother Pharmacol 24: 148–154.

  • Tsuji T, Todd R, Meyer C, McBride J, Liao PH, Huang MF, Chou MY, Donoff RB and Wong DT. . 1998 Oncogene 16: 3379–3385.

  • Tulchinsky EM, Georgiev GP and Lukanidin EM. . 1996 Oncogene 12: 1737–1745.

  • Veres DA, Wilkins L, Coble DW and Lyon SB. . 1989 J. Invest. Dermatol. 93: 687–690.

  • Verma AK, Ashendel CL and Boutwell RK. . 1980 Cancer Res. 40: 308–315.

  • Waltz DA, Natkin LR, Fujita RM, Wei Y and Chapman HA. . 1997 J. Clin. Invest. 100: 58–67.

  • Weeks CE, Herrmann AL, Nelson FR and Slaga TS. . 1982 Proc. Natl. Acad. Sci. USA 79: 6028–6032.

  • Wetters TvD, Brabant M and Coffino P. . 1989 Nucleic Acids Res. 23: 9843–9860.

  • Williams HK, Springall DR, Bhatnagar M and Polak JM. . 1995 J. Oral Pathol. Med. 24: 322–328.

  • Yebra MJ and Bhagwat AS. . 1995 Biochemistry 34: 14752–14757.

  • Zhang M, Maass N, Magit D and Sager R. . 1997 Cell Growth Differ 8: 179–186.

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Acknowledgements

We would like to thank Dr Philip Coffino for providing DFMO and his technical advice on ODC enzyme assay. We also thank Dr John LA Mitchell (Northern Illinois University) for providing the polyclonal antibody to ODC-Az detection, and Dr Keijiro Samejima for providing decarboxylated S-adenosylmethionine to HPLC analysis. This work was supported by Grants DE-12529 to T Tsuji, DE-12467 to DTW Wong, and DE-11983 to R Todd.

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Authors and Affiliations

  1. Department of Oral Medicine and Diagnostic Sciences, Division of Oral Pathology, Harvard School of Dental Medicine, Boston, 02115, Massachusetts, MA, USA

    Takanori Tsuji & David TW Wong

  2. Department of Oral Pathology, School of Dentistry, Showa University, Shinagawa, Tokyo, 142-8555, Japan

    Satomi Usui, Tadateru Aida & Tetsuhiko Tachikawa

  3. Department of Radiology, Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Guo-Fu Hu

  4. Department of Oral and Maxillofacial Surgery II, Okayama University Dental School, Okayama, 700-8525, Japan

    Akira Sasaki & Tomohiro Matsumura

  5. Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, 02114, Massachusetts, MA, USA

    Randy Todd

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Tsuji, T., Usui, S., Aida, T. et al. Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme. Oncogene 20, 24–33 (2001). https://doi.org/10.1038/sj.onc.1204051

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