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Promoter methylation study of the H37/RBM5 tumor suppressor gene from the 3p21.3 human lung cancer tumor suppressor locus

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Abstract

Loss of heterozygosity (LOH) at chromosome 3p21.3 is one of the most prevalent genetic disturbances occurring at the earliest stage of tumor development for a wide variety of human cancers, culminated in lung cancer. The 19 genes residing at 3p21.3 have been vigorously characterized for tumor suppressor activity and gene inactivation mechanism because of their potentially significant merits of clinical applications. Many of these 19 genes have been shown to manifest various growth inhibitory properties, however none of them are inactivated by coding mutations in their remaining allele as in the Knudson’s two- hits hypothesis. Thus far the most prevailing, alternative gene inactivation mechanism known for the 3p21.3 TSGs is epigenetic silencing by promoter hypermethylation. Previously, we have focused our investigation on one of the 19 genes at 3p21.3, H37/RBM5, and demonstrated its tumor suppressor activity both in vitro and in vivo as well as its mRNA/protein expression loss from the remaining allele in a majority of the primary lung tumors examined. The current study tested our hypothesis that the H37 inactivation in primary lung tumors may, as seen in most of the other 3p21.3 TSGs, be due to hypermethylation in its promoter CpG islands. Contrary to this most plausible postulation, however, we found no evidence of epigenetic gene silencing for the H37 TSG. Here we suggest some of the possible, further- alternative means of the H37 gene expression loss in tumor, including defects in transcription and post-transcriptional/translational modifications as well as mechanisms related to haploinsufficiency.

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References

  • Carboni GL, Gao B, Nishizaki M, Xu K, Minna JD, Roth JA, Ji L (2003) CACNA2D2-mediated apoptosis in NSCLC cells is associated with alterations of the intracellular calcium signaling and disruption of mitochondria membrane integrity. Oncogene 22:615–626

    Article  PubMed  CAS  Google Scholar 

  • Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP (2004) RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. Int J Cancer 109:839–847

    Article  PubMed  CAS  Google Scholar 

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25:315–319

    Article  PubMed  CAS  Google Scholar 

  • Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S, Pfeifer GP (2003) Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis. Histol Histopathol 18:665–677

    PubMed  CAS  Google Scholar 

  • Davis (1986) Basic methods in molecular biology. Elsevier, New York, pp 44–46

    Google Scholar 

  • Frost GI, Mohapatra G, Wong TM, Csoka AB, Gray JW, Stern R (2000) HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA. Oncogene 19:870–877

    Article  PubMed  CAS  Google Scholar 

  • Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM (1997) Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem 272:22322–22329

    Article  PubMed  CAS  Google Scholar 

  • Gu TL, Mercher T, Tyner JW, Goss VL, Walters DK, Cornejo MG, Reeves C, Popova L, Lee K, Heinrich MC, Rush J, Daibata M, Miyoshi I, Gilliland DG, Druker BJ, Polakiewicz RD (2007) A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia. Blood 110:323–333

    Article  PubMed  CAS  Google Scholar 

  • Hesson LB, Cooper WN, Latif F (2007) Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene 26:7283–7301

    Article  PubMed  CAS  Google Scholar 

  • Ji L, Minna JD, Roth JA (2005) 3p21.3 tumor suppressor cluster: prospects for translational applications. Future Oncol 1:79–92

    Article  PubMed  CAS  Google Scholar 

  • Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD (2002) Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Cancer Res 62:2715–2720

    PubMed  CAS  Google Scholar 

  • Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S (2006) Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer 119:99–107

    Article  PubMed  CAS  Google Scholar 

  • Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    Article  PubMed  Google Scholar 

  • Kusy S, Potiron V, Zeng C, Franklin W, Brambilla E, Minna J, Drabkin HA, Roche J (2005) Promoter characterization of Semaphorin SEMA3F, a tumor suppressor gene. Biochim Biophys Acta 1730:66–76

    PubMed  CAS  Google Scholar 

  • Lerman MI, Minna JD (2000) The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res 60:6116–6133

    PubMed  CAS  Google Scholar 

  • Li J, Wang F, Haraldson K, Protopopov A, Duh FM, Geil L, Kuzmin I, Minna JD, Stanbridge E, Braga E, Kashuba VI, Klein G, Lerman MI, Zabarovsky ER (2004) Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C. Cancer Res 64:6438–6443

    Article  PubMed  CAS  Google Scholar 

  • Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL (2005a) HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res 65:7782–7789

    Article  PubMed  CAS  Google Scholar 

  • Lokeshwar VB, Cerwinka WH, Lokeshwar BL (2005b) HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. Cancer Res 65:2243–2250

    Article  PubMed  CAS  Google Scholar 

  • Lokeshwar VB, Schroeder GL, Carey RI, Soloway MS, Iida N (2002) Regulation of hyaluronidase activity by alternative mRNA splicing. J Biol Chem 277:33654–33663

    Article  PubMed  CAS  Google Scholar 

  • Melki JR, Vincent PC, Brown RD, Clark SJ (2000) Hypermethylation of E-cadherin in leukemia. Blood 95:3208–3213

    PubMed  CAS  Google Scholar 

  • Melki JR, Vincent PC, Clark SJ (1999) Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 59:3730–3740

    PubMed  CAS  Google Scholar 

  • Nair PN, McArdle L, Cornell J, Cohn SL, Stallings RL (2007) High-resolution analysis of 3p deletion in neuroblastoma and differential methylation of the SEMA3B tumor suppressor gene. Cancer Genet Cytogenet 174:100–110

    Article  PubMed  CAS  Google Scholar 

  • Oh JJ, Boctor B, Jimenez CA, Lopez RC, Razfar A, Slamon DJ (2005) Use of low-melting-point primers for bisulfite genomic sequencing: analysis of the H37 lung cancer tumor suppressor gene promoter. Anal Biochem 343:347–349

    Article  PubMed  CAS  Google Scholar 

  • Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ (2006) 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res 66:3419–3427

    Article  PubMed  CAS  Google Scholar 

  • Oh JJ, West AR, Fishbein MC, Slamon DJ (2002) A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3. Cancer Res 62:3207–3213

    PubMed  CAS  Google Scholar 

  • Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33:49–54

    Article  PubMed  CAS  Google Scholar 

  • Shu Y, Rintala-Maki ND, Wall VE, Wang K, Goard CA, Langdon CE, Sutherland LC (2007) The apoptosis modulator and tumour suppressor protein RBM5 is a phosphoprotein. Cell Biochem Funct 25:643–653

    Article  PubMed  CAS  Google Scholar 

  • Song JZ, Stirzaker C, Harrison J, Melki JR, Clark SJ (2002) Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene 21:1048–1061

    Article  PubMed  CAS  Google Scholar 

  • Sutherland LC, Rintala-Maki ND, White RD, Morin CD (2005) RNA binding motif (RBM) proteins: a novel family of apoptosis modulators? J Cell Biochem 94:5–24

    Article  PubMed  CAS  Google Scholar 

  • Tischoff I, Markwarth A, Witzigmann H, Uhlmann D, Hauss J, Mirmohammadsadegh A, Wittekind C, Hengge UR, Tannapfel A (2005) Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int J Cancer 115:684–689

    Article  PubMed  CAS  Google Scholar 

  • Uno F, Sasaki J, Nishizaki M, Carboni G, Xu K, Atkinson EN, Kondo M, Minna JD, Roth JA, Ji L (2004) Myristoylation of the fus1 protein is required for tumor suppression in human lung cancer cells. Cancer Res 64:2969–2976

    Article  PubMed  CAS  Google Scholar 

  • Yi HM, Ren CP, Peng D, Zhou L, Li H, Yao KT (2007) Expression, loss of heterozygosity, and methylation of GNAT1 gene in nasopharyngeal carcinoma. Ai Zheng 26:9–14

    PubMed  CAS  Google Scholar 

  • Zabarovsky ER, Lerman MI, Minna JD (2002) Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 21:6915–6935

    Article  PubMed  CAS  Google Scholar 

  • Zhang WJ, Koltun WA, Tilberg AF, Page MJ, Chorney MJ (2000) Absence of GNAI2 codon 179 oncogene mutations in inflammatory bowel disease. Inflamm Bowel Dis 6:103–106

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We are deeply grateful to Mr. and Mrs. Werner and Mimi Wolfen for their abundant and heartfelt support towards lung cancer research which made this study possible. Grant support: Developmental Research Program Award from the University of California at Los Angeles Lung Cancer Specialized Programs of Research Excellence grant P50C A90388 (J.J. Oh), American Lung Association of California Research Grant (J.J. Oh), and the Wolfen Family Lung Cancer Clinical/Translational Research Program at University of California at Los Angeles Jonsson Comprehensive Cancer Center.

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Author notes

  1. Baher N. Boctor

    Present address: School of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA

  2. Cynthia A. Jimenez

    Present address: School of Medicine, University of California at San Francisco, San Francisco, CA, 94143, USA

Authors and Affiliations

  1. Division of Hematology/Oncology, School of Medicine, University of California at Los Angeles, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA

    Juliana J. Oh, Baher N. Boctor, Cynthia A. Jimenez, Roberto Lopez, Ashley K. Koegel, Eileen O. Taschereau, Diana T. Phan & Dennis J. Slamon

  2. Department of Molecular, Cell and Developmental Biology, Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    Steven E. Jacobsen

  3. School of Medicine, University of California at San Francisco, San Francisco, CA, 94143, USA

    Roberto Lopez

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  1. Juliana J. Oh
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Correspondence to Juliana J. Oh.

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Oh, J.J., Boctor, B.N., Jimenez, C.A. et al. Promoter methylation study of the H37/RBM5 tumor suppressor gene from the 3p21.3 human lung cancer tumor suppressor locus. Hum Genet 123, 55–64 (2008). https://doi.org/10.1007/s00439-007-0449-5

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  • DOI: https://doi.org/10.1007/s00439-007-0449-5

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