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Molecular Cancer
Published in: Molecular Cancer 1/2009

Open Access 01-12-2009 | Research

The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis

Authors: Mirco Menigatti, Elisa Cattaneo, Jacob Sabates-Bellver, Valery V Ilinsky, Philip Went, Federico Buffoli, Victor E Marquez, Josef Jiricny, Giancarlo Marra

Published in: Molecular Cancer | Issue 1/2009

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Abstract

Background

Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential.

Results

A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the p rotein- t yrosine p hosphatase r eceptor type R (PTPRR) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major PTPRR transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the PTPRR-1 isoform was inactivated in colorectal cancer cells as a result of de novo CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3. De novo methylation of the PTPRR-1 transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors.

Conclusions

Epigenetic downregulation of PTPRR seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway.
Appendix
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Literature
1.
2.
3.
Merlo LM, Pepper JW, Reid BJ, Maley CC: Cancer as an evolutionary and ecological process. Nat Rev Cancer. 2006, 6: 924-935. 10.1038/nrc2013CrossRefPubMed
4.
Sabates-Bellver J, Flier Van der LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M: Transcriptome profile of human colorectal adenomas. Mol Cancer Res. 2007, 5: 1263-1275. 10.1158/1541-7786.MCR-07-0267CrossRefPubMed
5.
Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T: Protein tyrosine phosphatases in the human genome. Cell. 2004, 117: 699-711. 10.1016/j.cell.2004.05.018CrossRefPubMed
6.
Hunter T: A thousand and one protein kinases. Cell. 1987, 50: 823-829. 10.1016/0092-8674(87)90509-5CrossRefPubMed
7.
Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature. 2001, 411: 355-365. 10.1038/35077225CrossRefPubMed
8.
Hendriks WJ, Elson A, Harroch S, Stoker AW: Protein tyrosine phosphatases: functional inferences from mouse models and human diseases. FEBS J. 2008, 275: 816-830. 10.1111/j.1742-4658.2008.06249.xCrossRefPubMed
9.
Tonks NK: Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 2006, 7: 833-846. 10.1038/nrm2039CrossRefPubMed
10.
Garcia JM, Silva J, Pena C, Garcia V, Rodriguez R, Cruz MA, Cantos B, Provencio M, Espana P, Bonilla F: Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004, 41: 117-124. 10.1002/gcc.20062CrossRefPubMed
11.
Motiwala T, Ghoshal K, Das A, Majumder S, Weichenhan D, Wu YZ, Holman K, James SJ, Jacob ST, Plass C: Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene. 2003, 22: 6319-6331. 10.1038/sj.onc.1206750PubMedCentralCrossRefPubMed
12.
Oka T, Ouchida M, Koyama M, Ogama Y, Takada S, Nakatani Y, Tanaka T, Yoshino T, Hayashi K, Ohara N: Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 2002, 62: 6390-6394.PubMed
13.
Xu S, Furukawa T, Kanai N, Sunamura M, Horii A: Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J Hum Genet. 2005, 50: 159-167. 10.1007/s10038-005-0235-yCrossRefPubMed
14.
Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S, Ptak J, Silliman N, Peters BA, Heijden van der MS: Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science. 2004, 304: 1164-1166. 10.1126/science.1096096CrossRefPubMed
15.
Ostman A, Hellberg C, Bohmer FD: Protein-tyrosine phosphatases and cancer. Nat Rev Cancer. 2006, 6: 307-320. 10.1038/nrc1837CrossRefPubMed
16.
Augustine KA, Silbiger SM, Bucay N, Ulias L, Boynton A, Trebasky LD, Medlock ES: Protein tyrosine phosphatase (PC12, Br7, S1) family: expression characterization in the adult human and mouse. Anat Rec. 2000, 258: 221-234. 10.1002/(SICI)1097-0185(20000301)258:3<221::AID-AR1>3.0.CO;2-WCrossRefPubMed
17.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q: Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007, 21: 1050-1063. 10.1101/gad.1524107PubMedCentralCrossRefPubMed
18.
Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, Farnham PJ: Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004, 18: 1592-1605. 10.1101/gad.1200204PubMedCentralCrossRefPubMed
19.
Hendriks WJ, Dilaver G, Noordman YE, Kremer B, Fransen JA: PTPRR protein tyrosine phosphatase isoforms and locomotion of vesicles and mice. Cerebellum. 2009, 8: 80-88. 10.1007/s12311-008-0088-yPubMedCentralCrossRefPubMed
20.
Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D: Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002, 16: 2893-2905. 10.1101/gad.1035902PubMedCentralCrossRefPubMed
21.
Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y: Role of histone H3 lysine 27 methylation in X inactivation. Science. 2003, 300: 131-135. 10.1126/science.1084274CrossRefPubMed
22.
Lindroth AM, Park YJ, McLean CM, Dokshin GA, Persson JM, Herman H, Pasini D, Miro X, Donohoe ME, Lee JT: Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus. PLoS Genet. 2008, 4: e1000145- 10.1371/journal.pgen.1000145PubMedCentralCrossRefPubMed
23.
Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK, Hermanson O, Rosenfeld MG: SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature. 2007, 450: 415-419. 10.1038/nature06270CrossRefPubMed
24.
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE: Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007, 39: 232-236. 10.1038/ng1950CrossRefPubMed
25.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM: The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006, 439: 871-874. 10.1038/nature04431CrossRefPubMed
26.
Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA: DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther. 2009, 8: 1579-1588. 10.1158/1535-7163.MCT-09-0013PubMedCentralCrossRefPubMed
27.
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998, 19: 187-191. 10.1038/561CrossRefPubMed
28.
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A: Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998, 393: 386-389. 10.1038/30764CrossRefPubMed
29.
Eswaran J, von Kries JP, Marsden B, Longman E, Debreczeni JE, Ugochukwu E, Turnbull A, Lee WH, Knapp S, Barr AJ: Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. Biochem J. 2006, 395: 483-491. 10.1042/BJ20051931PubMedCentralCrossRefPubMed
30.
Buschbeck M, Eickhoff J, Sommer MN, Ullrich A: Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway. J Biol Chem. 2002, 277: 29503-29509. 10.1074/jbc.M202149200CrossRefPubMed
31.
Munoz JJ, Tarrega C, Blanco-Aparicio C, Pulido R: Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents. Biochem J. 2003, 372: 193-201. 10.1042/BJ20021941PubMedCentralCrossRefPubMed
32.
Ogata M, Oh-hora M, Kosugi A, Hamaoka T: Inactivation of mitogen-activated protein kinases by a mammalian tyrosine-specific phosphatase, PTPBR7. Biochem Biophys Res Commun. 1999, 256: 52-56. 10.1006/bbrc.1999.0278CrossRefPubMed
33.
Pulido R, Zuniga A, Ullrich A: PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 1998, 17: 7337-7350. 10.1093/emboj/17.24.7337PubMedCentralCrossRefPubMed
34.
Chirivi RG, Noordman YE, Zee Van der CE, Hendriks WJ: Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice. J Neurochem. 2007, 101: 829-840. 10.1111/j.1471-4159.2006.04398.xCrossRefPubMed
35.
Balmanno K, Cook SJ: Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009, 16: 368-377. 10.1038/cdd.2008.148CrossRefPubMed
36.
Sodir NM, Chen X, Park R, Nickel AE, Conti PS, Moats R, Bading JR, Shibata D, Laird PW: Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. Cancer Res. 2006, 66: 8430-8438. 10.1158/0008-5472.CAN-06-1437CrossRefPubMed
37.
Weyden van der L, Arends MJ, Dovey OM, Harrison HL, Lefebvre G, Conte N, Gergely FV, Bradley A, Adams DJ: Loss of Rassf1a cooperates with Apc(Min) to accelerate intestinal tumourigenesis. Oncogene. 2008, 27: 4503-4508. 10.1038/onc.2008.94PubMedCentralCrossRefPubMed
38.
Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, Rosty C, Abal M, El Marjou F, Smits R: APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006, 131: 1096-1109. 10.1053/j.gastro.2006.08.011CrossRefPubMed
39.
Baylin SB, Ohm JE: Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?. Nat Rev Cancer. 2006, 6: 107-116. 10.1038/nrc1799CrossRefPubMed
40.
Feinberg AP, Ohlsson R, Henikoff S: The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006, 7: 21-33. 10.1038/nrg1748CrossRefPubMed
41.
Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, Pretlow TP, Yang B, Akiyama Y, Van Engeland M: Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004, 36: 417-422. 10.1038/ng1330CrossRefPubMed
42.
Flier Van der LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, Van Gijn ME, Suijkerbuijk S, Wetering Van de M, Marra G, Clevers H: The Intestinal Wnt/TCF Signature. Gastroenterology. 2007, 132: 628-632. 10.1053/j.gastro.2006.08.039CrossRefPubMed
43.
Aliaga JC, Deschenes C, Beaulieu JF, Calvo EL, Rivard N: Requirement of the MAP kinase cascade for cell cycle progression and differentiation of human intestinal cells. Am J Physiol. 1999, 277: G631-641.PubMed
44.
Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M: Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999, 18: 813-822. 10.1038/sj.onc.1202367CrossRefPubMed
45.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766CrossRefPubMed
46.
Malumbres M, Barbacid M: RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003, 3: 459-465. 10.1038/nrc1097CrossRefPubMed
47.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002, 418: 934- 10.1038/418934aCrossRefPubMed
48.
49.
Menigatti M, Truninger K, Gebbers JO, Marbet U, Marra G, Schar P: Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene. 2009, 28: 899-909. 10.1038/onc.2008.444CrossRefPubMed
50.
Fujimoto K, Beauchamp RD, Whitehead RH: Identification and isolation of candidate human colonic clonogenic cells based on cell surface integrin expression. Gastroenterology. 2002, 123: 1941-1948. 10.1053/gast.2002.37065CrossRefPubMed
51.
Marra G, D'Atri S, Corti C, Bonmassar L, Cattaruzza MS, Schweizer P, Heinimann K, Bartosova Z, Nystrom-Lahti M, Jiricny J: Tolerance of human MSH2 +/- lymphoblastoid cells to the methylating agent temozolomide. Proc Natl Acad Sci USA. 2001, 98: 7164-7169. 10.1073/pnas.121136498PubMedCentralCrossRefPubMed
Metadata
Title
The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis
Authors
Mirco Menigatti
Elisa Cattaneo
Jacob Sabates-Bellver
Valery V Ilinsky
Philip Went
Federico Buffoli
Victor E Marquez
Josef Jiricny
Giancarlo Marra
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2009
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-8-124

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