In the human placenta, DNA hypomethylation permits the expression of retrotransposon-derived genes that are normally silenced by methylation in somatic tissues. We previously identified hypomethylation of a retrotransposon-derived transcript of the voltage-gated potassium channel gene KCNH5 that is expressed only in human placenta. However, an RNA sequence from this placental-specific transcript has been reported in melanoma. This study examined the promoter methylation and expression of the retrotransposon-derived KCNH5 transcript in 25 melanoma cell lines to determine whether the acquisition of ‘placental’ epigenetic marks is a feature of melanoma. Methylation and gene expression analysis revealed hypomethylation of this retrotransposon in melanoma cell lines, particularly in those samples that express the placental KCNH5 transcript. Therefore we propose that hypomethylation of the placental-specific KCNH5 promoter is frequently associated with KCNH5 expression in melanoma cells. Our findings show that melanoma can develop hypomethylation of a retrotransposon-derived gene; a characteristic notably shared with the normal placenta.
References
[1]
Reiss D, Zhang Y, Mager DL (2007) Widely variable endogenous retroviral methylation levels in human placenta. Nucleic Acids Res 35: 4743–4754. doi: 10.1093/nar/gkm455
[2]
Okahara G, Matsubara S, Oda T, Sugimoto J, Jinno Y, et al. (2004) Expression analyses of human endogenous retroviruses (HERVs): tissue-specific and developmental stage-dependent expression of HERVs. Genomics 84: 982–990. doi: 10.1016/j.ygeno.2004.09.004
[3]
Kato N, Pfeifer-Ohlsson S, Kato M, Larsson E, Rydnert J, et al. (1987) Tissue-specific expression of human provirus ERV3 mRNA in human placenta: two of the three ERV3 mRNAs contain human cellular sequences. J Virol 61: 2182–2191.
[4]
Wilkinson DA, Goodchild NL, Saxton TM, Wood S, Mager DL (1993) Evidence for a functional subclass of the RTVL-H family of human endogenous retrovirus-like sequences. J Virol 67: 2981–2989.
[5]
Kim HS, Yi JM, Hirai H, Huh JW, Jeong MS, et al. (2006) Human Endogenous Retrovirus (HERV)-R family in primates: Chromosomal location, gene expression, and evolution. Gene 370: 34–42. doi: 10.1016/j.gene.2005.11.008
[6]
Shen HM, Nakamura A, Sugimoto J, Sakumoto N, Oda T, et al. (2006) Tissue specificity of methylation and expression of human genes coding for neuropeptides and their receptors, and of a human endogenous retrovirus K family. J Hum Genet 51: 440–450. doi: 10.1007/s10038-006-0382-9
[7]
Gama-Sosa MA, Wang RY, Kuo KC, Gehrke CW, Ehrlich M (1983) The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res 11: 3087–3095. doi: 10.1093/nar/11.10.3087
[8]
Hellmann-Blumberg U, Hintz MF, Gatewood JM, Schmid CW (1993) Developmental differences in methylation of human Alu repeats. Mol Cell Biol 13: 4523–4530.
[9]
Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, et al. (2000) An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74: 3321–3329. doi: 10.1128/jvi.74.7.3321-3329.2000
[10]
Mi S, Lee X, Li X, Veldman GM, Finnerty H, et al. (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403: 785–789.
[11]
Szpakowski S, Sun X, Lage JM, Dyer A, Rubinstein J, et al. (2009) Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements. Gene 448: 151–167. doi: 10.1016/j.gene.2009.08.006
[12]
Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400–5413. doi: 10.1038/sj.onc.1205651
[13]
Ross JP, Rand KN, Molloy PL (2010) Hypomethylation of repeated DNA sequences in cancer. Epigenomics 2: 245–269. doi: 10.2217/epi.10.2
[14]
Eden A, Gaudet F, Waghmare A, Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300: 455. doi: 10.1126/science.1083557
[15]
Ferretti C, Bruni L, Dangles-Marie V, Pecking AP, Bellet D (2007) Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update 13: 121–141. doi: 10.1093/humupd/dml048
[16]
Damsky CH, Fitzgerald ML, Fisher SJ (1992) Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest 89: 210–222. doi: 10.1172/jci115565
Macaulay EC, Weeks RJ, Andrews S, Morison IM (2011) Hypomethylation of functional retrotransposon-derived genes in the human placenta. Mamm Genome 22: 722–735. doi: 10.1007/s00335-011-9355-1
[19]
Meyer LR, Zweig AS, Hinrichs AS, Karolchik D, Kuhn RM, et al. (2013) The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41: D64–69. doi: 10.1093/nar/gks1048
[20]
Benson DA, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, et al. (2014) GenBank. Nucleic Acids Res 42: D32–37. doi: 10.1093/nar/gkt1030
[21]
Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, et al. (1999) Oncogenic potential of EAG K(+) channels. EMBO J 18: 5540–5547. doi: 10.1093/emboj/18.20.5540
[22]
Bauer CK, Schwarz JR (2001) Physiology of EAG K+ channels. J Membr Biol 182: 1–15.
[23]
Ludwig J, Weseloh R, Karschin C, Liu Q, Netzer R, et al. (2000) Cloning and functional expression of rat eag2, a new member of the ether-a-go-go family of potassium channels and comparison of its distribution with that of eag1. Mol Cell Neurosci 16: 59–70. doi: 10.1006/mcne.2000.0851
[24]
Rodriguez-Rasgado JA, Acuna-Macias I, Camacho J (2012) Eag1 Channels as Potential Cancer Biomarkers. Sensors 12: 5986–5995. doi: 10.3390/s120505986
[25]
Wadhwa S, Wadhwa P, Dinda AK, Gupta NP (2009) Differential expression of potassium ion channels in human renal cell carcinoma. Int Urol Nephrol 41: 251–257. doi: 10.1007/s11255-008-9459-z
[26]
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, et al. (2002) The human genome browser at UCSC. Genome Res 12: 996–1006. doi: 10.1101/gr.229102
[27]
Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, et al. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 99: 16899–16903. doi: 10.1073/pnas.242603899
[28]
(1964) Human Tissue Act.
[29]
Baguley BC, Marshall ES (2004) In vitro modelling of human tumour behaviour in drug discovery programmes. Eur J Cancer 40: 794–801. doi: 10.1016/j.ejca.2003.12.019
[30]
Marshall ES, Matthews JH, Shaw JH, Nixon J, Tumewu P, et al. (1994) Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays. Eur J Cancer 30A: 1370–1376. doi: 10.1016/0959-8049(94)90188-0
[31]
Stones CJ, Kim JE, Joseph WR, Leung E, Marshall ES, et al. (2013) Comparison of responses of human melanoma cell lines to MEK and BRAF inhibitors. Front Genet 4: 66. doi: 10.3389/fgene.2013.00066
[32]
Jeffs AR, Glover AC, Slobbe LJ, Wang L, He S, et al. (2009) A gene expression signature of invasive potential in metastatic melanoma cells. PLoS ONE 4: e8461. doi: 10.1371/journal.pone.0008461
[33]
Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Sayers EW (2009) GenBank. Nucleic Acids Res 37: D26–31. doi: 10.1093/nar/gkn723
[34]
Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J (2007) qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol 8: R19. doi: 10.1186/gb-2007-8-2-r19
[35]
Camacho J (2006) Ether a go-go potassium channels and cancer. Cancer Lett 233: 1–9. doi: 10.1016/j.canlet.2005.02.016
[36]
Farias LM, Ocana DB, Diaz L, Larrea F, Avila-Chavez E, et al. (2004) Ether a go-go potassium channels as human cervical cancer markers. Cancer Res 64: 6996–7001. doi: 10.1158/0008-5472.can-04-1204
[37]
Kunzelmann K (2005) Ion channels and cancer. J Membr Biol 205: 159–173. doi: 10.1007/s00232-005-0781-4
[38]
Pardo LA (2004) Voltage-gated potassium channels in cell proliferation. Physiology (Bethesda) 19: 285–292. doi: 10.1152/physiol.00011.2004
[39]
Hoffmann MJ, Schulz WA (2005) Causes and consequences of DNA hypomethylation in human cancer. Biochem Cell Biol 83: 296–321. doi: 10.1139/o05-036
[40]
Ehrlich M (2009) DNA hypomethylation in cancer cells. Epigenomics 1: 239–259. doi: 10.2217/epi.09.33
[41]
Schinke C, Mo Y, Yu Y, Amiri K, Sosman J, et al. (2010) Aberrant DNA methylation in malignant melanoma. Melanoma Res 20: 253–265. doi: 10.1097/cmr.0b013e328338a35a
[42]
Zendman AJ, de Wit NJ, van Kraats AA, Weidle UH, Ruiter DJ, et al. (2001) Expression profile of genes coding for melanoma differentiation antigens and cancer/testis antigens in metastatic lesions of human cutaneous melanoma. Melanoma Res 11: 451–459. doi: 10.1097/00008390-200110000-00003
[43]
Caballero OL, Chen YT (2009) Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100: 2014–2021. doi: 10.1111/j.1349-7006.2009.01303.x
[44]
Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5: 615–625. doi: 10.1038/nrc1669
[45]
Hoshimoto S, Kuo CT, Chong KK, Takeshima TL, Takei Y, et al. (2012) AIM1 and LINE-1 epigenetic aberrations in tumor and serum relate to melanoma progression and disease outcome. J Invest Dermatol 132: 1689–1697. doi: 10.1038/jid.2012.36
[46]
Bieche I, Laurent A, Laurendeau I, Duret L, Giovangrandi Y, et al. (2003) Placenta-specific INSL4 expression is mediated by a human endogenous retrovirus element. Biol Reprod 68: 1422–1429. doi: 10.1095/biolreprod.102.010322
[47]
Rawn SM, Cross JC (2008) The evolution, regulation, and function of placenta-specific genes. Annu Rev Cell Dev Biol 24: 159–181. doi: 10.1146/annurev.cellbio.24.110707.175418