Abstract
Epigenetic mechanisms play an important role in the regulation of gene expression and are critical for the function of normal physiological processes like cell proliferation, differentiation and morphogenesis. Alterations in epigenetic mechanisms contribute to the initiation and progression of various pathological conditions like genetic disorders, autoimmune diseases, aging and cancer. In this chapter, we discuss the different types of epigenetic mechanisms and how dysregulation of these mechanisms can lead to the initiation and development of various cancers. In addition, we highlight the importance of cancer stem cell (CSC) markers that serve as putative biomarkers for cancer diagnosis and prognosis, and epigenetic variations of these markers in cancer. Given the importance of microRNAs in gene regulation and cancer, we discuss the regulation of various tumor suppressor microRNAs by CSC markers and vice versa. A thorough knowledge on these aspects is critical in the development of therapeutics that can target cancer stem cells.
Keywords
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Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96:8681–8686
Lao VV, Grady WM (2011) Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8:686–700
Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36
Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162
Baylin SB (2005) DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2(Suppl 1):S4–S11
Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C et al (2006) Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res 66:8462–9468
Long C, Yin B, Lu Q, Zhou X, Hu J, Yang Y et al (2007) Promoter hypermethylation of the RUNX3 gene in esophageal squamous cell carcinoma. Cancer Invest 25:685–690
Akiyama Y, Watkins N, Suzuki H, Jair KW, van Engeland M, Esteller M et al (2003) GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol Cell Biol 23:8429–8439
Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G et al (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res 62:6456–6461
Bonisch C, Hake SB (2012) Histone H2A variants in nucleosomes and chromatin: more or less stable? Nucleic Acids Res 40:10719–10741
Witcher M, Emerson BM (2009) Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell 34:271–284
Sporn JC, Jung B (2012) Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer. Am J Pathol 180:2516–2526
McCabe MT, Brandes JC, Vertino PM (2009) Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 15:3927–3937
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988
Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737
Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037
Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007
Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40:915–920
Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA (2011) Interconversion between intestinal stem cell populations in distinct niches. Science 334:1420–1424
May R, Riehl TE, Hunt C, Sureban SM, Anant S, Houchen CW (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26:630–637
Rezza A, Skah S, Roche C, Nadjar J, Samarut J, Plateroti M (2010) The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation. J Cell Sci 123:3256–3265
Sureban SM, May R, George RJ, Dieckgraefe BK, McLeod HL, Ramalingam S et al (2008) Knockdown of RNA binding protein Musashi-1 leads to tumor regression in vivo. Gastroenterology 134:1448–1458, e2
Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea–a paradigm shift. Cancer Res 66:1883–1890; discussion 1895
Reynolds BA, Weiss S (1996) Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175:1–13
Weiss S, Reynolds BA, Vescovi AL, Morshead C, Craig CG, van der Kooy D (1996) Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19:387–393
Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270
Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95
Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A et al (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712
Olsen CL, Hsu PP, Glienke J, Rubanyi GM, Brooks AR (2004) Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC Cancer 4:43
Takeda K, Kinoshita I, Shimizu Y, Matsuno Y, Shichinohe T, Dosaka-Akita H (2011) Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. Anticancer Res 31:263–270
Li DW, Tang HM, Fan JW, Yan DW, Zhou CZ, Li SX et al (2010) Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol 136:997–1006
Harada Y, Kijima K, Shinmura K, Sakata M, Sakuraba K, Yokomizo K et al (2011) Methylation of the homeobox gene, HOPX, is frequently detected in poorly differentiated colorectal cancer. Anticancer Res 31:2889–2892
Gagliardi G, Goswami M, Passera R, Bellows CF (2012) DCLK1 immunoreactivity in colorectal neoplasia. Clin Exp Gastroenterol 5:35–42
Kagara N, Huynh KT, Kuo C, Okano H, Sim MS, Elashoff D et al (2012) Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer. Am J Pathol 181:257–267
Jiang L, Li J, Song L (2009) Bmi-1, stem cells and cancer. Acta Biochim Biophys Sin 41:527–534
Marquardt JU, Factor VM, Thorgeirsson SS (2010) Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications. J Hepatol 53:568–577
So AY, Jung JW, Lee S, Kim HS, Kang KS (2011) DNA methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS One 6:e19503
Sureban SM, May R, Mondalek FG, Qu D, Ponnurangam S, Pantazis P et al (2011) Nanoparticle-based delivery of siDCAMKL-1 increases microRNA-144 and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism. J Nanobiotechnol 9:40
Sureban SM, May R, Lightfoot SA, Hoskins AB, Lerner M, Brackett DJ et al (2011) DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer Res 71:2328–2338
Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T et al (2013) Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet 45(1):98–103
Andresen K, Boberg KM, Vedeld HM, Honne H, Hektoen M, Wadsworth CA et al (2012) Novel target genes and a valid biomarker panel identified for cholangiocarcinoma. Epigenetics 7:1249–1257
Sureban SM, May R, Qu D, Ali N, Houchen CW (2012) Regulation of pluripotency markers by DCLK1 in pancreatic cancer. Pancreas 41:1407
Glazer RI, Vo DT, Penalva LO (2012) Musashi1: an RBP with versatile functions in normal and cancer stem cells. Front Biosci 17:54–64
Vo DT, Qiao M, Smith AD, Burns SC, Brenner AJ, Penalva LO (2011) The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs. RNA Biol 8:817–828
Sureban SM, May R, Qu DF, Asfa S, Anant S, Houchen CW (2011) Knockdown of Musashi-1 results in tumor growth arrest through inhibition of c-Myc, Notch-1 and EMT by let-7a, miR-144 and miR-200a microRNAs dependent mechanisms respectively. Gastroenterology 140:S48
Yi JM, Tsai HC, Glockner SC, Lin S, Ohm JE, Easwaran H et al (2008) Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68:8094–8103
Liu C, Tang DG (2011) MicroRNA regulation of cancer stem cells. Cancer Res 71:5950–5954
Tong A, Gou L, Lau QC, Chen B, Zhao X, Li J et al (2009) Proteomic profiling identifies aberrant epigenetic modifications induced by hepatitis B virus X protein. J Proteome Res 8:1037–1046
Park SY, Kwon HJ, Choi Y, Lee HE, Kim SW, Kim JH et al (2012) Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes. Mod Pathol 25:185–196
Peter ME (2009) Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 8:843–852
Acknowledgements
This work was supported by National Institutes of Health (NIH) and National Cancer Institute (NCI) grants: CA-137482 (CWH); Oklahoma Center for the Advancement of Science and Technology (CWH). We would like to thank Dr. Ilangovan Ramachandran and Nathaniel Weygant for reviewing this book chapter.
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Sureban, S.M., Qu, D., Houchen, C.W. (2013). Epigenetic Variations of Stem Cell Markers in Cancer. In: Sarkar, F. (eds) Epigenetics and Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6612-9_7
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DOI: https://doi.org/10.1007/978-94-007-6612-9_7
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