Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/MicroRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT)

Journal of Biological Chemistry

Volumn 287, Issue 50, 2012, Pages 42180-42194

  Grassian, Alexandra R ^a   Lin, Fallon ^a   Barrett, Rosemary ^a   Liu, Yue ^a   Jiang, Wei ^a   Korpal, Manav ^a   Astley, Holly ^b   Gitterman, Daniel ^b   Henley, Thomas ^b   Howes, Rob ^b   Levell, Julian ^a   Korn, Joshua M ^a   Pagliarini, Raymond ^a  

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b Molecular Biotechnology Center   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CELL LINES; CELLULAR MORPHOLOGY; DOWN-REGULATION; EPITHELIAL CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; GENES ENCODING; ISOCITRATE DEHYDROGENASE; MICRORNAS; MUTANT CELLS; SIGNALING PATHWAYS; TUMORIGENESIS; UP-REGULATION; WILD TYPES;

TRANSCRIPTION FACTORS;

CELL CULTURE;

2 HYDROXYGLUTARIC ACID; ISOCITRATE DEHYDROGENASE 1; ISOCITRATE DEHYDROGENASE 2; MICRORNA 200; TRANSCRIPTION FACTOR ZEB1;

ARTICLE; BIOACCUMULATION; BREAST EPITHELIUM; CANCER CELL; CARCINOGENESIS; CELL DISRUPTION; CELL STRUCTURE; COLORECTAL CANCER; CONTROLLED STUDY; DOWN REGULATION; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; GENE; GENE CONTROL; GENE EXPRESSION; GENE FUNCTION; GENE MUTATION; GENE SILENCING; IDH1 GENE; IDH2 GENE; INTRACELLULAR SIGNALING; MUTATIONAL ANALYSIS; PHENOTYPE; PRIORITY JOURNAL; TRANSCRIPTION REGULATION;

AMINO ACID SUBSTITUTION; CELL LINE, TUMOR; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUTARATES; HOMEODOMAIN PROTEINS; HUMANS; ISOCITRATE DEHYDROGENASE; MICRORNAS; MUTATION, MISSENSE; NEOPLASM PROTEINS; NEOPLASMS; RNA, NEOPLASM; TRANSCRIPTION FACTORS; UP-REGULATION;

EID: 84870677094     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.417832     Document Type: Article

References (66)

1. Arai, M., Nobusawa, S., Ikota, H., Takemura, S., and Nakazato, Y. (2012) Frequent IDH1/2 mutations in intracranial chondrosarcoma: a possible diagnostic clue for its differentiation from chordoma. Brain Tumor Pathol. 1-6
2. Cairns, R. A., Iqbal, J., Lemonnier, F., Kucuk, C., de Leval, L., Jais, J. P., Parrens, M., Martin, A., Xerri, L., Brousset, P., Chan, L. C., Chan, W. C., Gaulard, P., and Mak, T. W. (2012) IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119, 1901-1903
3. Hayden, J. T., Frühwald, M. C., Hasselblatt, M., Ellison, D. W., Bailey, S., and Clifford, S. C. (2009) Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children. Cell Cycle 8, 1806-1807
4. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I. M., Gallia, G. L., Olivi, A., McLendon, R., Rasheed, B. A., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D. A., Tekleab, H., Diaz, L. A., Jr., Hartigan, J., Smith, D. R., Strausberg, R. L., Marie, S. K., Shinjo, S. M., Yan, H., Riggins, G. J., Bigner, D. D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V. E., and Kinzler, K. W. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812
5. Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K. W., Velculescu, V. E., Vogelstein, B., and Bigner, D. D. (2009) IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773
6. Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., Rabinowitz, J. D., Carroll, M., Su, S. M., Sharp, K. A., Levine, R. L., and Thompson, C. B. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225-234
7. Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Locke, D. P., Magrini, V. J., Abbott, R. M., Vickery, T. L., Reed, J. S., Robinson, J. S., Wylie, T., Smith, S. M., Carmichael, L., Eldred, J. M., Harris, C. C., Walker, J., Peck, J. B., Du, F., Dukes, A. F., Sanderson, G. E., Brummett, A. M., Clark, E., McMichael, J. F., Meyer, R. J., Schindler, J. K., Pohl, C. S., Wallis, J. W., Shi, X., Lin, L., Schmidt, H., Tang, Y., Haipek, C., Wiechert, M. E., Ivy, J. V., Kalicki, J., Elliott, G., Ries, R. E., Payton, J. E., Westervelt, P., Tomasson, M. H., Watson, M. A., Baty, J., Heath, S., Shannon, W. D., Nagarajan, R., Link, D. C., Walter, M. J., Graubert, T. A., DiPersio, J. F., Wilson, R. K., and Ley, T. J. (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058-1066
8. Gross, S., Cairns, R. A., Minden, M. D., Driggers, E. M., Bittinger, M. A., Jang, H. G., Sasaki, M., Jin, S., Schenkein, D. P., Su, S. M., Dang, L., Fantin, V. R., and Mak, T. W. (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339-344
9. Amary, M. F., Bacsi, K., Maggiani, F., Damato, S., Halai, D., Berisha, F., Pollock, R., O'Donnell, P., Grigoriadis, A., Diss, T., Eskandarpour, M., Presneau, N., Hogendoorn, P. C., Futreal, A., Tirabosco, R., and Flanagan, A. M. (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334-343
10. Borger, D. R., Tanabe, K. K., Fan, K. C., Lopez, H. U., Fantin, V. R., Straley, K. S., Schenkein, D. P., Hezel, A. F., Ancukiewicz, M., Liebman, H. M., Kwak, E. L., Clark, J. W., Ryan, D. P., Deshpande, V., Dias-Santagata, D., Ellisen, L. W., Zhu, A. X., and Iafrate, A. J. (2012) Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72-79
11. Wang, P., Dong, Q., Zhang, C., Kuan, P. F., Liu, Y., Jeck, W. R., Andersen, J. B., Jiang, W., Savich, G. L., Tan, T. X., Auman, J. T., Hoskins, J. M., Misher, A. D., Moser, C. D., Yourstone, S. M., Kim, J. W., Cibulskis, K., Getz, G., Hunt, H. V., Thorgeirsson, S. S., Roberts, L. R., Ye, D., Guan, K. L., Xiong, Y., Qin, L. X., and Chiang, D. Y. (2012) Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene doi: 10.1038/onc.2012.315
12. Lopez, G. Y., Reitman, Z. J., Solomon, D., Waldman, T., Bigner, D. D., McLendon, R. E., Rosenberg, S. A., Samuels, Y., and Yan, H. (2010) IDH1(R132) mutation identified in one human melanoma metastasis but not correlated with metastases to the brain. Biochem. Biophys. Res. Commun. 398, 585-587
13. Ghiam, A. F., Cairns, R. A., Thoms, J., Dal Pra, A., Ahmed, O., Meng, A., Mak, T. W., and Bristow, R. G. (2012) IDH mutation status in prostate cancer. Oncogene 31, 3826
14. Taylor, B. S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B. S., Arora, V. K., Kaushik, P., Cerami, E., Reva, B., Antipin, Y., Mitsiades, N., Landers, T., Dolgalev, I., Major, J. E., Wilson, M., Socci, N. D., Lash, A. E., Heguy, A., Eastham, J. A., Scher, H. I., Reuter, V. E., Scardino, P. T., Sander, C., Sawyers, C. L., and Gerald, W. L. (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11-22
15. Kang, M. R., Kim, M. S., Oh, J. E., Kim, Y. R., Song, S. Y., Seo, S. I., Lee, J. Y., Yoo, N. J., and Lee, S. H. (2009) Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 125, 353-355
16. Sequist, L. V., Heist, R. S., Shaw, A. T., Fidias, P., Rosovsky, R., Temel, J. S., Lennes, I. T., Digumarthy, S., Waltman, B. A., Bast, E., Tammireddy, S., Morrissey, L., Muzikansky, A., Goldberg, S. B., Gainor, J., Channick, C. L., Wain, J. C., Gaissert, H., Donahue, D. M., Muniappan, A., Wright, C., Willers, H., Mathisen, D. J., Choi, N. C., Baselga, J., Lynch, T. J., Ellisen, L. W., Mino-Kenudson, M., Lanuti, M., Borger, D. R., Iafrate, A. J., Engelman, J. A., and Dias-Santagata, D. (2011) Implementing multiplexed genotyping of non-small cell lung cancers into routine clinical practice. Ann. Oncol. 22, 2616-2624
17. Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D., Leary, R. J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S. D., Willis, J., Dawson, D., Willson, J. K., Gazdar, A. F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B. H., Bachman, K. E., Papadopoulos, N., Vogelstein, B., Kinzler, K. W., and Velculescu, V. E. (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274 (Pubitemid 44571966)
18. Dang, L., Jin, S., and Su, S. M. (2010) IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387-397
19. Yen, K. E., and Schenkein, D. P. (2012) Cancer-associated isocitrate dehydrogenase mutations. Oncologist 17, 5-8
20. Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., Marks, K. M., Prins, R. M., Ward, P. S., Yen, K. E., Liau, L. M., Rabinowitz, J. D., Cantley, L. C., Thompson, C. B., Vander Heiden, M. G., and Su, S. M. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739-744
21. Struys, E. A., Salomons, G. S., Achouri, Y., Van Schaftingen, E., Grosso, S., Craigen, W. J., Verhoeven, N. M., and Jakobs, C. (2005) Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 76, 358-360 (Pubitemid 40129562)
22. Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S., and Jakobs, C. (2012) Progress in understanding 2-hydroxyglutaric acidurias. J. Inherit. Metab. Dis. 35, 571-587
23. Loenarz, C., and Schofield, C. J. (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat. Chem. Biol. 4, 152-156 (Pubitemid 351264133)
24. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S. H., Ito, S., Yang, C., Wang, P., Xiao, M. T., Liu, L. X., Jiang, W. Q., Liu, J., Zhang, J. Y., Wang, B., Frye, S., Zhang, Y., Xu, Y. H., Lei, Q. Y., Guan, K. L., Zhao, S. M., and Xiong, Y. (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30
25. Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., Travins, J., Weiss, S., Looper, R., Ligon, K. L., Verhaak, R. G., Yan, H., and Kaelin, W. G., Jr. (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488
26. Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., Wellen, K. E., O'Rourke, D. M., Berger, S. L., Chan, T. A., Levine, R. L., Mellinghoff, I. K., and Thompson, C. B. (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474-478
27. Deneberg, S., Guardiola, P., Lennartsson, A., Qu, Y., Gaidzik, V., Blanchet, O., Karimi, M., Bengtzén, S., Nahi, H., Uggla, B., Tidefelt, U., Höglund, M., Paul, C., Ekwall, K., Döhner, K., and Lehmann, S. (2011) Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Blood 118, 5573-5582
28. Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., Verhaak, R. G., Hoadley, K. A., Hayes, D. N., Perou, C. M., Schmidt, H. K., Ding, L., Wilson, R. K., Van Den Berg, D., Shen, H., Bengtsson, H., Neuvial, P., Cope, L. M., Buckley, J., Herman, J. G., Baylin, S. B., Laird, P. W., and Aldape, K. (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510-522
29. Chowdhury, R., Yeoh, K. K., Tian, Y. M., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K., Li, X. S., Woon, E. C., Yang, M., McDonough, M. A., King, O. N., Clifton, I. J., Klose, R. J., Claridge, T. D., Ratcliffe, P. J., Schofield, C. J., and Kawamura, A. (2011) The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463-469
30. Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., Tallman, M. S., Sun, Z., Wolniak, K., Peeters, J. K., Liu, W., Choe, S. E., Fantin, V. R., Paietta, E., Löwenberg, B., Licht, J. D., Godley, L. A., Delwel, R., Valk, P. J., Thompson, C. B., Levine, R. L., and Melnick, A. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553-567
31. Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., Ding, J., Lei, Q., Guan, K. L., and Xiong, Y. (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261-265
32. Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., You-Ten, A., Li, W. Y., Schalm, S., Su, S. M., Virtanen, C., Reifenberger, G., Ohashi, P. S., Barber, D. L., Figueroa, M. E., Melnick, A., Zúñiga- Pflücker, J. C., and Mak, T. W. (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656-659
33. Sasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I., Cairns, R. A., McCracken, S., Wakeham, A., Haight, J., Ten, A. Y., Snow, B., Ueda, T., Inoue, S., Yamamoto, K., Ko, M., Rao, A., Yen, K. E., Su, S. M., and Mak, T. W. (2012) D-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038-2049
34. Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W., Lu, C., Ward, P. S., Thompson, C. B., Kaufman, A., Guryanova, O., Levine, R., Heguy, A., Viale, A., Morris, L. G., Huse, J. T., Mellinghoff, I. K., and Chan, T. A. (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479-483
35. Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., Reddy, A., Liu, M., Murray, L., Berger, M. F., Monahan, J. E., Morais, P., Meltzer, J., Korejwa, A., Jané-Valbuena, J., Mapa, F. A., Thibault, J., Bric-Furlong, E., Raman, P., Shipway, A., Engels, I. H., Cheng, J., Yu, G. K., Yu, J., Aspesi, P., Jr., de Silva, M., Jagtap, K., Jones, M. D., Wang, L., Hatton, C., Palescandolo, E., Gupta, S., Mahan, S., Sougnez, C., Onofrio, R. C., Liefeld, T., MacConaill, L., Winckler, W., Reich, M., Li, N., Mesirov, J. P., Gabriel, S. B., Getz, G., Ardlie, K., Chan, V., Myer, V. E., Weber, B. L., Porter, J., Warmuth, M., Finan, P., Harris, J. L., Meyerson, M., Golub, T. R., Morrissey, M. P., Sellers, W. R., Schlegel, R., and Garraway, L. A. (2012) The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity. Nature 483, 603-607
36. Kohli, M., Rago, C., Lengauer, C., Kinzler, K. W., and Vogelstein, B. (2004) Facile methods for generating human somatic cell gene knockouts using recombinant adeno-associated viruses. Nucleic Acids Res. 32, e3
37. Debnath, J., Muthuswamy, S. K., and Brugge, J. S. (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256-268 (Pubitemid 36677560)
38. Grassian, A. R., Metallo, C. M., Coloff, J. L., Stephanopoulos, G., and Brugge, J. S. (2011) Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 25, 1716-1733
39. Wiederschain, D., Chen, L., Johnson, B., Bettano, K., Jackson, D., Taraszka, J., Wang, Y. K., Jones, M. D., Morrissey, M., Deeds, J., Mosher, R., Fordjour, P., Lengauer, C., and Benson, J. D. (2007) Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Mol. Cell. Biol. 27, 4968-4979 (Pubitemid 47016145)
40. Taube, J. H., Herschkowitz, J. I., Komurov, K., Zhou, A. Y., Gupta, S., Yang, J., Hartwell, K., Onder, T. T., Gupta, P. B., Evans, K. W., Hollier, B. G., Ram, P. T., Lander, E. S., Rosen, J. M., Weinberg, R. A., and Mani, S. A. (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl. Acad. Sci. U.S.A. 107, 15449-15454
41. Blick, T., Hugo, H., Widodo, E., Waltham, M., Pinto, C., Mani, S. A., Weinberg, R. A., Neve, R. M., Lenburg, M. E., and Thompson, E. W. (2010) Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J. Mammary Gland Biol. Neoplasia 15, 235-252
42. Loboda, A., Nebozhyn, M. V., Watters, J. W., Buser, C. A., Shaw, P. M., Huang, P. S., Van't Veer, L., Tollenaar, R. A., Jackson, D. B., Agrawal, D., Dai, H., and Yeatman, T. J. (2011) EMT is the dominant program in human colon cancer. BMC Med. Genomics 4, 9
43. Wiederschain, D., Wee, S., Chen, L., Loo, A., Yang, G., Huang, A., Chen, Y., Caponigro, G., Yao, Y. M., Lengauer, C., Sellers, W. R., and Benson, J. D. (2009) Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle 8, 498-504
44. Wee, S., Wiederschain, D., Maira, S. M., Loo, A., Miller, C., deBeaumont, R., Stegmeier, F., Yao, Y. M., and Lengauer, C. (2008) PTEN-deficient cancers depend on PIK3CB. Proc. Natl. Acad. Sci. U.S.A. 105, 13057-13062
45. Capper, D., Zentgraf, H., Balss, J., Hartmann, C., and von Deimling, A. (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 118, 599-601
46. Kalluri, R., and Weinberg, R. A. (2009) The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420-1428
47. Schmalhofer, O., Brabletz, S., and Brabletz, T. (2009) E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 28, 151-166
48. Park, S. M., Gaur, A. B., Lengyel, E., and Peter, M. E. (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894-907 (Pubitemid 351482843)
49. Korpal, M., Lee, E. S., Hu, G., and Kang, Y. (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910-14914
50. Hurteau, G. J., Carlson, J. A., Spivack, S. D., and Brock, G. J. (2007) Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 67, 7972-7976 (Pubitemid 47395127)
51. Gregory, P. A., Bert, A. G., Paterson, E. L., Barry, S. C., Tsykin, A., Farshid, G., Vadas, M. A., Khew-Goodall, Y., and Goodall, G. J. (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593-601 (Pubitemid 351627379)
52. Christoffersen, N. R., Silahtaroglu, A., Orom, U. A., Kauppinen, S., and Lund, A. H. (2007) miR-200b mediates post-transcriptional repression of ZFHX1B. RNA 13, 1172-1178 (Pubitemid 47080461)
53. Burk, U., Schubert, J., Wellner, U., Schmalhofer, O., Vincan, E., Spaderna, S., and Brabletz, T. (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582-589 (Pubitemid 351772923)
54. Brabletz, S., and Brabletz, T. (2010) The ZEB/miR-200 feedback loop - a motor of cellular plasticity in development and cancer? EMBO Rep. 11, 670-677
55. Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., and Ashworth, A. (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111-1115 (Pubitemid 351317441)
56. Popovici-Muller, J., Saunders, J. O., Salituro, F. G., Travins, J. M., Yan, S., Zhao, F., Gross, S., Dang, L., Yen, K. E., Yang, H., Straley, K. S., Jin, S., Kunii, K., Fantin, V. R., Zhang, S., Pan, Q., Shi, D., Biller, S. A., and Su, S. M. (2012) Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med. Chem. Lett. 3, 850-855
57. Duncan, C. G., Barwick, B. G., Jin, G., Rago, C., Kapoor-Vazirani, P., Powell, D. R., Chi, J. T., Bigner, D. D., Vertino, P. M., and Yan, H. (2012) A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res., in press
58. Hathaway, N. A., Bell, O., Hodges, C., Miller, E. L., Neel, D. S., and Crabtree, G. R. (2012) Dynamics and memory of heterochromatin in living cells. Cell 149, 1447-1460
59. Singh, A., and Settleman, J. (2010) EMT, cancer stem cells and drug resistance. An emerging axis of evil in the war on cancer. Oncogene 29, 4741-4751
60. Scheel, C., and Weinberg, R. A. (2012) Cancer stem cells and epithelialmesenchymal transition. Concepts and molecular links. Semin. Cancer Biol. 22, 396-403
61. Oishi, N., Kumar, M. R., Roessler, S., Ji, J., Forgues, M., Budhu, A., Zhao, X., Andersen, J. B., Ye, Q. H., Jia, H. L., Qin, L. X., Yamashita, T., Goo Woo, H., Jun Kim, Y., Kaneko, S., Tang, Z. Y., Thorgeirsson, S. S., and Wei Wang, X. (2012) Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatology 2012 Jun 18. doi: 10.1002/hep.25890
62. Sellner, L., Capper, D., Meyer, J., Langhans, C. D., Hartog, C. M., Pfeifer, H., Serve, H., Ho, A. D., Okun, J. G., Krämer, A., and Von Deimling, A. (2010) Increased levels of 2-hydroxyglutarate inAMLpatients with IDH1- R132H and IDH2-R140Q mutations. Eur. J. Haematol. 85, 457-459
63. Chou, W. C., Lei, W. C., Ko, B. S., Hou, H. A., Chen, C. Y., Tang, J. L., Yao, M., Tsay, W., Wu, S. J., Huang, S. Y., Hsu, S. C., Chen, Y. C., Chang, Y. C., Kuo, K. T., Lee, F. Y., Liu, M. C., Liu, C. W., Tseng, M. H., Huang, C. F., and Tien, H. F. (2011) The prognostic impact and stability of isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25, 246-253
64. Herranz, H., and Cohen, S. M. (2010) MicroRNAs and gene regulatory networks. Managing the impact of noise in biological systems. Genes Dev. 24, 1339-1344
65. Krol, J., Loedige, I., and Filipowicz, W. (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597-610
66. Yan, Z., Shah, P. K., Amin, S. B., Samur, M. K., Huang, N., Wang, X., Misra, V., Ji, H., Gabuzda, D., and Li, C. (2012) Integrative analysis of gene and miRNA expression profiles with transcription factor-miRNA feed-forward loops identifies regulators in human cancers. Nucleic Acids Res. 40, e135