Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.
References
[1]
Jovanovic J, Ronneberg JA, Tost J, Kristensen V (2010) The epigenetics of breast cancer. Mol Oncol 4: 242–254. doi: 10.1016/j.molonc.2010.04.002
[2]
Ting AH, McGarvey KM, Baylin SB (2006) The cancer epigenome–components and functional correlates. Genes Dev 20: 3215–3231. doi: 10.1101/gad.1464906
[3]
Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128: 683–692. doi: 10.1016/j.cell.2007.01.029
[4]
Dedeurwaerder S, Fumagalli D, Fuks F (2011) Unravelling the epigenomic dimension of breast cancers. Curr Opin Oncol 23: 559–565. doi: 10.1097/cco.0b013e32834bd481
[5]
Huang Y, Nayak S, Jankowitz R, Davidson NE, Oesterreich S (2011) Epigenetics in breast cancer: what's new? Breast Cancer Res 13: 225. doi: 10.1186/bcr2925
[6]
Szyf M (2012) DNA methylation signatures for breast cancer classification and prognosis. Genome Med 4: 26. doi: 10.1186/gm325
[7]
Connolly R, Stearns V (2012) Epigenetics as a Therapeutic Target in Breast Cancer. J Mammary Gland Biol Neoplasia.
[8]
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. doi: 10.1038/nm0797-730
Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98: 1777–1785. doi: 10.1093/jnci/djj495
[11]
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, et al. (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672–679. doi: 10.1093/jnci/djn123
[12]
Yu F, Yao H, Zhu P, Zhang X, Pan Q, et al. (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131: 1109–1123. doi: 10.1016/j.cell.2007.10.054
[13]
Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, et al. (2007) WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A 104: 618–623. doi: 10.1073/pnas.0606599104
[14]
Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58: 267–284. doi: 10.1146/annurev.med.58.062105.204854
[15]
Ailles LE, Weissman IL (2007) Cancer stem cells in solid tumors. Curr Opin Biotechnol 18: 460–466. doi: 10.1016/j.copbio.2007.10.007
[16]
Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26: 2813–2820. doi: 10.1200/jco.2008.16.3931
[17]
Mimeault M, Hauke R, Mehta PP, Batra SK (2007) Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med 11: 981–1011. doi: 10.1111/j.1582-4934.2007.00088.x
[18]
Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5: 593–605. doi: 10.1038/nri1667
[19]
Liu B, Mink S, Wong KA, Stein N, Getman C, et al. (2004) PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat. Immunol. 5: 891–898. doi: 10.1038/ni1104
[20]
Liu B, Yang R, Wong KA, Getman C, Stein N, et al. (2005) Negative regulation of NF-kappaB signaling by PIAS1. Mol. Cell. Biol. 25: 1113–1123. doi: 10.1128/mcb.25.3.1113-1123.2005
[21]
Tahk S, Liu B, Chernishof V, Wong KA, Wu H, et al. (2007) Control of specificity and magnitude of NF-kB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proc. Natl Acad. Sci. USA 104: 11643–11648. doi: 10.1073/pnas.0701877104
[22]
Liu B, Yang Y, Chernishof V, Loo RR, Jang H, et al. (2007) Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell 129: 903–914. doi: 10.1016/j.cell.2007.03.056
[23]
Liu B, Shuai K (2008) Targeting the PIAS1 SUMO ligase pathway to control inflammation. Trends Pharmacol Sci 29: 505–509. doi: 10.1016/j.tips.2008.07.008
[24]
Liu B, Tahk S, Yee KM, Fan G, Shuai K (2010) The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330: 521–525. doi: 10.1126/science.1193787
[25]
Loke SL, Neckers LM, Schwab G, Jaffe ES (1988) c-myc protein in normal tissue. Effects of fixation on its apparent subcellular distribution. Am J Pathol 131: 29–37.
[26]
Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, et al. (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9: 391–403. doi: 10.1016/j.ccr.2006.03.030
[27]
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, et al. (2007) ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell 1: 555–567. doi: 10.1016/j.stem.2007.08.014
[28]
Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, et al. (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17: 1253–1270. doi: 10.1101/gad.1061803
[29]
Dontu G, Liu S, Wicha MS (2005) Stem cells in mammary development and carcinogenesis: implications for prevention and treatment. Stem Cell Rev 1: 207–213. doi: 10.1385/scr:1:3:207
[30]
Jonsson M, Dejmek J, Bendahl PO, Andersson T (2002) Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res 62: 409–416.
[31]
Mandelin E, Lassus H, Seppala M, Leminen A, Gustafsson JA, et al. (2003) Glycodelin in ovarian serous carcinoma: association with differentiation and survival. Cancer Res 63: 6258–6264.
[32]
Hautala LC, Koistinen R, Seppala M, Butzow R, Stenman UH, et al. (2008) Glycodelin reduces breast cancer xenograft growth in vivo. Int J Cancer 123: 2279–2284. doi: 10.1002/ijc.23773
[33]
Sakuma M, Akahira J, Ito K, Niikura H, Moriya T, et al. (2007) Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer. Cancer Sci 98: 380–386. doi: 10.1111/j.1349-7006.2007.00394.x
[34]
Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, et al. (2001) Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res 61: 2782–2787.
[35]
Inoue M, Takahashi K, Niide O, Shibata M, Fukuzawa M, et al. (2005) LDOC1, a novel MZF-1-interacting protein, induces apoptosis. FEBS Lett 579: 604–608. doi: 10.1016/j.febslet.2004.12.030
[36]
Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434: 843–850. doi: 10.1038/nature03319
[37]
Huang H, He X (2008) Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 20: 119–125. doi: 10.1016/j.ceb.2008.01.009
[38]
Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, et al. (2008) Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452: 650–653. doi: 10.1038/nature06835
[39]
Ying J, Li H, Chen YW, Srivastava G, Gao Z, et al. (2007) WNT5A is epigenetically silenced in hematologic malignancies and inhibits leukemia cell growth as a tumor suppressor. Blood 110: 4130–4132. doi: 10.1182/blood-2007-06-094870
[40]
Ying J, Li H, Yu J, Ng KM, Poon FF, et al. (2008) WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 14: 55–61. doi: 10.1158/1078-0432.ccr-07-1644
[41]
Yu J, Leung WK, Ebert MP, Leong RW, Tse PC, et al. (2003) Absence of cyclin D2 expression is associated with promoter hypermethylation in gastric cancer. Br J Cancer 88: 1560–1565.
[42]
Li LC, Chui R, Nakajima K, Oh BR, Au HC, et al. (2000) Frequent methylation of estrogen receptor in prostate cancer: correlation with tumor progression. Cancer Res 60: 702–706.
[43]
Wang D, Zhou J, Liu X, Lu D, Shen C, et al. (2013) Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability. Proc Natl Acad Sci U S A 110: 5516–5521. doi: 10.1073/pnas.1216596110
[44]
Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4: e115. doi: 10.1371/journal.pbio.0040115
[45]
Roarty K, Serra R (2007) Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development 134: 3929–3939. doi: 10.1242/dev.008250
[46]
Olson DJ, Gibo DM, Saggers G, Debinski W, Kumar R (1997) Reversion of uroepithelial cell tumorigenesis by the ectopic expression of human wnt-5a. Cell Growth Differ 8: 417–423.
[47]
Jonsson M, Andersson T (2001) Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells. J Cell Sci 114: 2043–2053.
[48]
Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, et al. (2003) Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4: 349–360. doi: 10.1016/s1535-6108(03)00268-x
[49]
Blanc E, Goldschneider D, Douc-Rasy S, Benard J, Raguenez G (2005) Wnt-5a gene expression in malignant human neuroblasts. Cancer Lett 228: 117–123. doi: 10.1016/j.canlet.2004.11.061
[50]
Liu B, Shuai K (2008) Regulation of the sumoylation system in gene expression. Curr Opin Cell Biol 20: 288–293. doi: 10.1016/j.ceb.2008.03.014
[51]
Liu B, Liao J, Rao X, Kushner SA, Chung CD, et al. (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Natl Acad. Sci.. USA 95: 10626–10631. doi: 10.1073/pnas.95.18.10626
[52]
Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM (1998) Development of a self-inactivating lentivirus vector. J Virol 72: 8150–8157.
