Modulation of cell death pathways in cancer stem cells: Targeting histone demethylases


Cancer stem cells (CSCs) are tumor initiating cells within the tumor mass; that play a critical role in cancer pathogenesis. CSCs regulate cancer cell survival, metastatic potential, resistance to conventional radio-chemotherapy, disease relapse and poor prognosis. Recent studies have established that the drug resistant cancers and cancer cell lines possess high stem cell like traits compared to their drug sensitive counterparts. Histone demethylases are recently been linked to drug induced reversible tolerant state in cancers. Lysine histone demethylases are enzymes those demethylate lysines in histones and can act as transcriptional repressors or activators. Apart from histones other cellular proteins like E2F1, Rb, STAT3 and p53 are also regulated by methylation and demethylation cycles. In cancer cells these enzymes regulate cell survival, migration, invasion, and proliferation. This review summarizes the current progress of research on the role of histone demethylases in supporting drug tolerant cancer stem cell state and their potential as a drug target.

Share and Cite:

Thakur, R. and Mishra, D. (2012) Modulation of cell death pathways in cancer stem cells: Targeting histone demethylases. Advances in Bioscience and Biotechnology, 3, 720-730. doi: 10.4236/abb.2012.326093.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Nguyen, L.V., Vanner, R., Dirks, P., Eaves, C.J. (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer. 12(2):133-43.
[2] Baccelli, I., Trumpp, A. (2012) The evolving concept of cancer and metastasis stem cells. J Cell Biol. 198(3):281-93.
[3] Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., Dirks, P.B. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research. 63 (18): 5821–8
[4] Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. PNAS. 100 (7): 3983–8.
[5] O'Brien, C.A., Pollett, A., Gallinger, S., Dick, J.E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445 (7123): 106–10.
[6] Zhang, S., Balch, C., Chan, M.W., Lai, H.C., Matei, D., Schilder, J.M., Yan, P.S., Huang, T.H., Nephew, K.P. (2008). Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Research. 68 (11): 4311–20.
[7] Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (February 2007). "Identification of pancreatic cancer stem cells. Cancer Research. 67 (3): 1030–7. doi:10.1158/0008-5472.CAN-06-2030. PMID 17283135.
[8] Schatton ,T., Murphy, G.F., Frank, N.Y., Yamaura, K., Waaga-Gasser, A.M., Gasser, M., Zhan, Q., Jordan, S., Duncan, L.M., Weishaupt, C., Fuhlbrigge, R.C., Kupper, T.S., Sayegh, M.H., Frank, M.H. (2008). Identification of cells initiating human melanomas. Nature. 451 (7176): 345–9.
[9] Boiko, A.D., Razorenova, O.V., van de Rijn, M., Swetter, S.M., Johnson, D.L., Ly, D.P., Butler, P.D., Yang, G.P., Joshua, B., Kaplan, M.J., Longaker, M.T., Weissman, I.L. (2010). Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 466 (7302): 133–7.
[10] Civenni, G., Walter, A., Kobert, N., Mihic-Probst, D., Zipser, M., Belloni, B., Seifert, B., Moch, H., Dummer, R., van den Broek, M., Sommer, L. (2011). Human CD271-Positive Melanoma Stem Cells Associated with Metastasis Establish Tumor Heterogeneity and Long-Term Growth. Cancer Res. 71 (8): 3098–109.
[11] Matsui, W., Huff, C.A., Wang, Q., et al. (2004). Characterization of clonogenic multiple myeloma cells. Blood. 103 (6): 2332–6.
[12] Singh, S.K.; Clarke, I.D.; Hide, T.; Dirks, P.B. (2004) Cancer stem cells in nervous system tumors. Oncogene. 23, 7267–7273.
[13] Vercauteren, S.M.; Sutherland, H.J. (2001) CD133 (AC133) expression on AML cells and progenitors. Cytotherapy. 3, 449–459.
[14] Matsui, W., Wang, Q., Barber, J.P., et al. (2008). Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 68 (1): 190–7.
[15] Oh, S.Y., Kang, H.J., Kim, Y.S., Kim, H., Lim, Y.C. (2012) CD44-negative cells in head and neck squamous carcinoma also have stem-cell like traits. Eur J Cancer. Jul 5. [Epub ahead of print] PubMed PMID: 22770891.
[16] Eyler, C.E; Rich, J.N. (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845.
[17] Li, X.; Lewi, M.T.; Huang, J.; Gutierrez, C.; Osborne, C.K.; Wu, M.; Hilsenbeck, S.G.; Pavlick, A.; Xiaomei Zhang, X.; Chamness, G.C.; Wong, H.; Rosen, J.; Chang, J.C. (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst. 100, 672–679.
[18] Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444, 756–760.
[19] Mitra, A., Conway, C., Walker, C., Cook, M., Powell, B. (2010) Melanoma sentinel node biopsy and prediction models for relapse and overall survival. Br J Cancer. 103(8): 1229–1236.
[20] Markopoulos, C.J. (2010) minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: efficacy review of AI trials. Cancer Metastasis Rev. 29(4):581-94.
[21] Saphner, T., Tormey, D.C., Gray, R. (1996) Annual hazard rates of recurrence for breast cancer after primary therapy. Journal of Clinical Oncology. 14(10): 2738–2746.
[22] Mansell J, Monypenny IJ, Skene AI, Abram P, Carpenter R, Gattuso JM, et al. (2009) Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer. Breast Cancer Research and Treatment. 117(1):91–98.
[23] Frisch, S. M. and Francis, H. (1994) Disruption of epithelial cell-matrix interactions induces apoptosis, Journal of Cell Biology. 124(4):619–626.
[24] Meredith, J. E., Fazeli, B., and Schwartz, M. A. (1993) The extracellular matrix as a cell survival factor, Molecular Biology of the Cell. 4(9):953–961.
[25] Sethi, T., Rintoul, R. C., Moore, S. M. et al. (1999) Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo, Nature Medicine. 5(6): 662–668.
[26] Konopleva, M.Y., Jordan, C.T. (2011) Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol. 29(5):591-9.
[27] Selvaggi, G., Novello, S., Torri, V., Leonardo, E., De Giuli, P., Borasio, P., Mossetti, C., Ardissone, F., Lausi, P., Scagliotti, GV. (2004) Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol. 15(1):28-32.
[28] Boudreau, N., Sympson, C.J., Werb, Z., Bissell, M.J. (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science. 267(5199):891-3.
[29] Qu, Y.T., Li, X.M., Xu, O., Wang, M.X., Lu, X.Y. (2012) Impacts of hypoxia on the features and chemoresistance of cancer stem cells in Hep-2 cells and underlying mechanism. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 47(3):228-33.
[30] Frolova, O., Samudio, I., Benito, J.M., Jacamo, R., Kornblau, S.M., Markovic, A., Schober, W.,Lu, H., Qiu, Y.H., Buglio, D., McQueen, T., Pierce, S., Shpall, E., Konoplev, S., Thomas, D.,Kantarjian, H., Lock, R., Andreeff, M., Konopleva, M. (2012) Regulation of HIF-1α signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment. Cancer Biol Ther.1; 13(10):858-70.
[31] Frisch, S.M., Vuori, K., Ruoslahti, E., Chan-Hui, P.Y. (1996) Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 134(3):793-9.
[32] Frisch, S.M., Screaton, R.A. (2001) Anoikis mechanisms. Curr Opin Cell Biol. 13(5):555-62.
[33] Kim, Y.N., Koo, K.H., Sung, J.Y., Yun, U.J., Kim, H. (2012) Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol. 306879.
[34] Ahmed, N., Abubaker, K., Findlay, J., Quinn, M. (2010) Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets. 10(3):268-78.
[35] Chuthapisith, S., Eremin, J., El-Sheemey, M., Eremin, O. (2010) Breast cancer chemoresistance: emerging importance of cancer stem cells. Surg Oncol. 19(1):27-32.
[36] May, C.D., Sphyris, N., Evans, K.W., Werden, S.J., Guo, W., Mani, S.A. (2011) Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res. 13(1):202.
[37] Singh, A., Settleman, J. (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 29(34):4741-51.
[38] Mani, S.A., Guo, W., Liao, M.J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F.,Zhang, C.C., Shipitsin, M., Campbell, L.L., Polyak, K., Brisken, C., Yang, J., Weinberg. R.A. (2008)The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133(4):704-15.
[39] Sarrio, D., Franklin, C.K., Mackay, A., Reis-Filho, J.S., Isacke, C.M. (2012) Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties. Stem Cells. 30(2):292-303.
[40] Lane, A.A., Chabner, B.A. (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 27(32):5459-68.
[41] Gravina, G.L., Festuccia, C., Marampon, F., Popov, V.M., Pestell, R.G., Zani, B.M., Tombolini, V. (2010) Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation. Mol Cancer. 9:305.
[42] Varier, R.A., Timmers, H.T. (2011) Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta. 1815(1):75-89.
[43] Tian, X., Fang, J. (2007) Current perspectives on histone demethylases. Acta Biochim Biophys Sin (Shanghai). 39(2):81-8.
[44] Trojer, P., Reinberg, D. (2006) Histone lysine demethylases and their impact on epigenetics. Cell. 125(2):213-7.
[45] Cloos, P.A., Christensen, J., Agger, K., Helin, K. (2008) Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22(9):1115-40.
[46] Shi, Y. (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet. 8(11):829-33.
[47] Kampranis, S.C., Tsichlis, P.N. (2009) Histone demethylases and cancer. Adv Cancer Res. 102:103-69.
[48] Lim, S., Metzger, E., Schüle, R., Kirfel, J., Buettner, R. (2010) Epigenetic regulation of cancer growth by histone demethylases. Int J Cancer. 127(9):1991-8.
[49] Agger, K., Christensen, J., Cloos, P.A., Helin, K. (2008) The emerging functions of histone demethylases. Curr Opin Genet Dev. 18(2):159-68.
[50] Klose, R.J., Zhang, Y. (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol; 8:307–18.
[51] Loh, Y.H., Zhang, W., Chen, X., George, J., Ng, H.H. (2007) Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 21:2545-2557.
[52] Christensen, J., Agger, K., Cloos, P.A., Pasini, D., Rose, S., Sennels, L., Rappsilber, J., Hansen, K.H., Salcini, A.E., Helin, K. (2007) RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 128:1063-1076.
[53] Osawa, T., Muramatsu, M., Wang, F., Tsuchida, R., Kodama, T.Minami, T., Shibuya, M. (2011) Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via down-regulating angiogenesis. Proc Natl Acad Sci U S A. 108(51):20725-9.
[54] Lu, Y., Chu, A., Turker, M.S., Glazer, P.M. (2011) Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol. 31(16):3339-50.
[55] Kottakis, F., Polytarchou, C., Foltopoulou, P., Sanidas, I., Kampranis, S.C., Tsichlis, P.N. (2011) FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell. 43(2):285-98.
[56] 56. Wong, P.P., Miranda, F., Chan, K.V., Berlato, C., Hurst, H.C., Scibetta, A.G. (2012) Histone demethylase KDM5B collaborates with TFAP2C and Myc to repress the cell cycle inhibitor p21(cip) (CDKN1A). Mol Cell Biol. 32(9):1633-44.
[57] Svotelis, A., Bianco, S., Madore, J., Huppé, G., Nordell-Markovits, A., Mes-Masson, A.M.,Gévry, N. (2011) H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERα ligand dependency. EMBO J. 30(19):3947-61.
[58] Lim, S., Janzer, A., Becker, A., Zimmer, A., Schüle, R., Buettner, R., Kirfel, J,. (2010)Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 31(3):512-20.
[59] Mitra, D., Das, P.M., Huynh, F.C., Jones, F.E. (2011) Jumonji/ARID1 B (JARID1B) protein promotes breast tumor cell cycle progression through epigenetic repression of microRNA let-7e. J Biol Chem. 286(47):40531-5.
[60] Huang, J., Sengupta, R., Espejo, A.B., Lee, M.G., Dorsey, J.A., Richter, M., Opravil, S., Shiekhattar, R., Bedford, M.T., Jenuwein, T., Scoumanne, A., Chen, X. (2007) The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners. J Biol Chem. 282(21):15471-5.
[61] Berger, S.L. (2007) p53 is regulated by the lysine demethylase LSD1. Nature. 449(7158):105-8.
[62] Gartel, A.L., Tyner, A.L. (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 1(8):639-49.
[63] Viale, A., De Franco, F., Orleth, A., Cambiaghi, V., Giuliani, V., Bossi, D., Ronchini, C., Ronzoni, S., Muradore, I., Monestiroli, S., Gobbi, A., Alcalay, M., Minucci, S., Pelicci, P.G. (2009) Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature. 457(7225):51-6.
[64] Harris, W.J., Huang, X., Lynch, J.T., Spencer, G.J., Hitchin, J.R., Li, Y., Ciceri, F., Blaser, J.G., Greystoke, B.F., Jordan, A.M., Miller, C.J., Ogilvie, D.J., Somervaille, T.C. (2012) The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 21(4):473-87.
[65] Henglein, B,, Chenivesse, X., Wang, J., Eick, D., Bréchot, C. (1994) Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc Natl Acad Sci U S A. 91(12):5490-4.
[66] Holbro, T., Hynes, N.E. (2004) ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 44:195-217.
[67] Suzuki, A., Horiuchi, A., Ashida, T., Miyamoto, T., Kashima, H., Nikaido, T., Konishi. I.,Shiozawa, T. (2010) Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up-regulation of an Akt-binding protein, periplakin. J Cell Mol Med. 14(9):2305-17.
[68] Tan, M., Yu, D. (2007) Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Adv Exp Med Biol. 608:119-29
[69] Lu, D., Carson, D.A. (2011) Inhibition of Wnt signaling and cancer stem cells. Oncotarget. 2(8):587.
[70] Huang, Y., Stewart, T.M., Wu, Y., Baylin, S.B., Marton, L.J., Perkins, B., Jones, R.J., Woster, P.M., Casero, R.A. Jr. (2009) Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res. 15(23):7217–28.
[71] Chung, M.T., Lai, H.C., Sytwu, H.K., Yan, M.D., Shih, Y.L., Chang, C.C., Yu, M.H., Liu, H.S., Chu, D.W., Lin, Y.W. (2009) SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. Gynecol Oncol. 112(3):646-53.
[72] DiPaola, R.S., Aisner, J. (1999) Overcoming bcl-2- and p53-mediated resistance in prostate cancer. Semin Oncol. 26(1 Suppl 2):112-6.
[73] Johnson, S.M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K.L., Brown, D., Slack, F.J. (2005) RAS is regulated by the let-7 microRNA family.Cell. 120(5):635-47.
[74] Kumar, M.S., Erkeland, S.J., Pester, R.E., Chen, C.Y., Ebert, M.S., Sharp, P.A., Jacks, T. (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci U S A. 105(10):3903-8
[75] He, X.Y., Chen, J.X., Zhang, Z., Li, C.L., Peng, Q.L., Peng, H.M. (2010) The let-7a microRNA protects from growth of lung carcinoma by suppression of k-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol. 136(7):1023-8
[76] Kooistra, S.M., Helin, K. (2012) Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol. 13(5):297-311.
[77] Kontaki, H., Talianidis, I. (2010) Lysine methylation regulates E2F1-induced cell death.Mol Cell. 39(1):152-60.
[78] Stiewe, T., Pützer, B.M. (2000) Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet. 26(4):464-9
[79] Sharma, S.V., Lee, D.Y., Li, B., Quinlan, M.P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M.A., Wong, K.K., Brandstetter, K., Wittner, B,.Ramaswamy, S., Classon, M., Settleman, J. (2010) A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 141(1):69-80.
[80] 80. Wang, J., Lu, F., Ren, Q., Sun, H., Xu. Z., Lan, R., Liu, Y., Ward, D., Quan, J., Ye, T., Zhang, H. (2011) Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res. 71(23):7238-49.
[81] Harris, W.J., Huang, X., Lynch, J.T., Spencer, G.J., Hitchin, J.R., Li, Y., Ciceri, F., Blaser, J.G., Greystoke, B.F., Jordan, A.M., Miller, C.J., Ogilvie, D.J., Somervaille, T.C. (2012) The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 21(4):473-87.
[82] Lv, T., Yuan, D., Miao, X., Lv, Y., Zhan, P., et al. (2012) Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer. PLoS ONE 7(4): e35065. doi:10.1371/journal.pone.0035065
[83] Schenk, T., Chen, WC., Gullner, S., Howell, L., Jin, L., Hebestreit, K., Klein, HU., Popescu, A.C., Burnet,t A., Mills, K., Casero, R.A. Jr., Marton, L., Woster, P., Minden, M.D., Dugas, M., Wang, J.C., Dick, J.E., Müller-Tidow, C., Petrie, K., Zelent, A. (2012) Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 18(4):605-11.
[84] Metzger, E., Wissmann, M., Yin, N., Müller, J,M., Schneider, R., Peters, A.H., Günther, T., Buettner, R., Schüle, R. (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 437:436-439.
[85] Kahl, P., Gullotti, L., Heukamp, L.C., Wolf, S., Friedrichs, N., Vorreuther, R., Solleder, G., Bastian, P.J., Ellinger, J., Metzger, E., Schüle, R., Buettner, R. (2006) Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 66(23):11341-7.
[86] Willmann D, Lim S, Wetzel S, Metzger E, Jandausch A, Wilk W, Jung M, Forne I, Imhof A, Janzer A, Kirfel J, Waldmann H, Schüle R, Buettner R. Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. Int J Cancer. 2012 Mar 24. doi: 10.1002/ijc.27555.
[87] Wang, Y., Zhang, H., Chen, Y., Sun, Y., Yang, F., Yu, W., Liang, J., Sun, L., Yang, X., Shi, L., Li, R., Li, Y., Zhang, Y., Li, Q., Yi, X., Shang, Y. (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell. 138(4):660-72.
[88] Lim, S., Janzer, A., Becker, A., Zimmer A, Schüle R, Buettner R, Kirfel J.Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 2010 Mar;31(3):512-20.
[89] He, J., Nguyen, A.T., Zhang, Y. (2011) KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood. 117(14):3869-80.
[90] Frescas, D., Guardavaccaro, D., Bassermann, F., Koyama-Nasu, R., Pagano, M. (2007) JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature. 450(7167):309-13.
[91] Krieg, A.J., Rankin, E.B., Chan, D., Razorenova, O., Fernandez, S., Giaccia, A.J. (2010) Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol. 30(1):344-53.
[92] Du, Z.M., Hu, L.F., Wang, H.Y., Yan, L.X, Zeng, Y.X., Shao, J.Y., Ernberg, I. (2011) Upregulation of MiR-155 in nasopharyngeal carcinoma is partly driven by LMP1 and LMP2A and downregulates a negative prognostic marker JMJD1A. PLoS One. 6(4):e19137
[93] Lim, S., Metzger, E., Schüle, R., Kirfel, J., Buettner, R. (2010) Epigenetic regulation of cancer growth by histone demethylases. Int J Cancer.127(9):1991-8.Review.
[94] Beyer, S., Kristensen, M.M., Jensen, K.S., Johansen, J.V., Staller, P. (2008) The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J Biol Chem. 283(52):36542-52.
[95] Cloos, P.A., Christensen, J., Agger, K., Maiolica, A., Rappsilber, J., Antal, T., Hansen, K.H., Helin, K. (2006) The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature. 442(7100):307-11.
[96] Italiano, A., Attias, R., Aurias, A., Pérot, G., Burel-Vandenbos, F., Otto, J., Venissac, N., Pedeutour, F. (2006) Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C. Cancer Genet Cytogenet. 167(2):122-30.
[97] Liu, G., Bollig-Fischer, A., Kreike, B., van de Vijver, M.J., Abrams, J., Ethier, S.P., Yang, Z.Q. (2009) Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene. 28(50):4491-500.
[98] Ehrbrecht, A., Müller, U., Wolter, M., Hoischen, A., Koch, A., Radlwimmer, B., Actor, B., Mincheva, A., Pietsch, T., Lichter, P., Reifenberger, G., Weber, R.G. (2006) Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol. 208(4):554-63.
[99] Yamane, K., Tateishi, K., Klose, R.J., Fang, J., Fabrizio, L.A., Erdjument-Bromage, H., Taylor-Papadimitriou, J., Tempst, P., Zhang, Y. (2007) PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol Cell. 25(6):801-12.
[100] Barrett, A., Madsen, B., Copier, J., Lu, P.J., Cooper, L., Scibetta, A.G., Burchell, J., Taylor-Papadimitriou, J. (2002) PLU-1 nuclear protein, which is upregulated in breast cancer, shows restricted expression in normal human adult tissues: a new cancer/testis antigen? Int J Cancer. 101(6):581-8.
[101] Xiang, Y., Zhu, Z., Han, G., Ye, X., Xu, B., Peng, Z., Ma, Y., Yu, Y., Lin, H., Chen, A.P., Chen, C.D. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19226-31.
[102] van Haaften, G. (2009) Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 41(5):521-3.
[103] Gui, Y. (2011) Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 43(9):875-8.
[104] Anderton, J.A., Bose, S., Vockerodt, M., Vrzalikova, K., Wei, W., Kuo, M., Helin, K., Christensen, J., Rowe, M., Murray, P.G., Woodman, C.B. (2011) The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma. Oncogene. 30(17):2037-43.
[105] Xiang, Y., Zhu, Z., Han, G., Lin, H., Xu, L., Chen, C.D. (2007) JMJD3 is a histone H3K27 demethylase. Cell Res. 2007. 17(10):850-7.
[106] Hsia, D.A., Tepper, C.G., Pochampalli, M.R., Hsia, E.Y., Izumiya, C., Huerta, S.B., Wright, M.E., Chen, H.W., Kung, H.J., Izumiya, Y. (2010) KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc Natl Acad Sci U S A. 2010 May 25;107(21):9671-6.
[107] Gallinari, P., Di Marco, S., Jones, P., Pallaoro, M., Steinkühler, C. (2007) HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res. 17(3):195-211.
[108] Peng, L., Seto, E. (2011) Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb Exp Pharmacol. 206:39-56
[109] Singh, M.M., Manton, C.A., Bhat, K.P., Tsai, W.W., Aldape, K., Barton, M.C., Chandra, J. (2011)Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol. 2011 Aug;13(8):894-903.
[110] Huang, Y., Vasilatos, S.N., Boric, L., Shaw, P.G., Davidson, N.E. (2012) Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat. 131(3):777-89.
[111] Styczynski, J., and Drewa, T. (2007) Leukemic stem cells: from metabolic pathways and signaling to a new concept of drug resistance targeting. Acta Biochim. Pol., 54, 717-726.
[112] Fodde, R., and Brabletz, T. (2007) Wnt/β-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol., 19, 150-158.
[113] Zhou, J., Wulfkuhle, J., Zhang, H., Gu, P., Yang, Y., Deng, J., Margolick, J.B., Liotta, L.A., Petricoin, E. 3rd, Zhang, Y. (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stemlike cells is required for viability and maintenance. Proc. Natl. Acad. Sci. USA, 104, 16158-16163
[114] Peacock, C.D., Wang, Q., Gesell, G.S., Corcoran-Schwartz, I.M., Jones, E., Kim, J., Devereux, W.L., Rhodes, J.T., Huff, C.A., Beachy, P.A., Watkins, D.N., Matsui, W. (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci US A. 104(10):4048-53.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.