SUV420H2 is an epigenetic regulator of epithelial/ mesenchymal states in pancreatic cancer

Journal of Cell Biology

Volumn 217, Issue 2, 2018, Pages 763-777

  Viotti, Manuel ^a   Wilson, Catherine ^a   McCleland, Mark ^a   Koeppen, Hartmut ^a   Haley, Benjamin ^a   Jhunjhunwala, Suchit ^a   Klijn, Christiaan ^a   Modrusan, Zora ^a   Arnott, David ^a   Classon, Marie ^a   Stephan, Jean Philippe ^a,b   Mellman, Ira ^a  

^a GENENTECH INC   (United States)

^b INSTITUT DE RECHERCHES INTERNATIONALES SERVIER   (France)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE METHYLTRANSFERASE; HISTONE METHYLTRANSFERASE SUV420H2; UNCLASSIFIED DRUG; HISTONE LYSINE METHYLTRANSFERASE; SUV420H2 PROTEIN, HUMAN;

ARTICLE; CANCER GROWTH; CARCINOGENESIS; CONTROLLED STUDY; DRUG SENSITIVITY; ENZYME ACTIVITY; ENZYME REGULATION; EPIGENETICS; EPITHELIAL MESENCHYMAL TRANSITION; GENE KNOCKDOWN; GENE SILENCING; HISTONE METHYLATION; HUMAN; HUMAN CELL; HUMAN TISSUE; PANCREAS CANCER; PANCREATIC CANCER CELL LINE; PRIORITY JOURNAL; TUMOR BIOPSY; TUMOR INVASION; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; METABOLISM; PANCREAS TUMOR; PATHOLOGY; TUMOR CELL LINE;

CELL LINE, TUMOR; EPIGENESIS, GENETIC; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; HISTONE-LYSINE N-METHYLTRANSFERASE; HUMANS; PANCREATIC NEOPLASMS;

EID: 85041647751     PISSN: 00219525     EISSN: 15408140     Source Type: Journal    
DOI: 10.1083/jcb.201705031     Document Type: Article

References (71)

1. Arumugam, T., V. Ramachandran, K.F. Fournier, H. Wang, L. Marquis, J.L. Abbruzzese, G.E. Gallick, C.D. Logsdon, D.J. McConkey, and W. Choi. 2009. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69:5820-5828. https ://doi. org /10. 1158 /0008-5472. CAN-08-2819
2. Bebee, T.W., J.W. Park, K.I. Sheridan, C.C. Warzecha, B.W. Cieply, A.M. Rohacek, Y. Xing, and R.P. Carstens. 2015. The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. Elife. 4:e08954. https ://doi. org /10. 7554 /eLife. 08954
3. Bierhoff, H., M.A. Dammert, D. Brocks, S. Dambacher, G. Schotta, and I. Grummt. 2014. Quiescence-induced LncRNAs trigger H4K20. trimethylation and transcriptional silencing. Mol. Cell. 54:675-682. https ://doi. org /10. 1016 /j. molcel. 2014. 03. 032
4. Brabletz, T., F. Hlubek, S. Spaderna, O. Schmalhofer, E. Hiendlmeyer, A. Jung, and T. Kirchner. 2005. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 179:56-65. https ://doi. org /10. 1159 /000084509
5. Cao, Q., J. Yu, S.M. Dhanasekaran, J.H. Kim, R.S. Mani, S.A. Tomlins, R. Mehra, B. Laxman, X. Cao, J. Yu, et al. 2008. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 27:7274-7284. https ://doi. org /10. 1038 /onc. 2008. 333
6. Cerami, E., J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, A. Jacobsen, C.J. Byrne, M.L. Heuer, E. Larsson, et al. 2012. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401-404. https ://doi. org /10. 1158 /2159-8290. CD-12-0095
7. Chen, D.S., and I. Mellman. 2017. Elements of cancer immunity and the cancer-immune set point. Nature. 541:321-330. https ://doi. org /10. 1038. /nature21349
8. Dawson, M.A., and T. Kouzarides. 2012. Cancer epigenetics: from mechanism to therapy. Cell. 150:12-27. https ://doi. org /10. 1016 /j. cell. 2012. 06. 013
9. Deer, E.L., J. González-Hernández, J.D. Coursen, J.E. Shea, J. Ngatia, C.L. Scaife, M.A. Firpo, and S.J. Mulvihill. 2010. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 39:425-435. https :// doi. org /10. 1097 /MPA. 0b013e3181c15963
10. Dong, C., Y. Wu, Y. Wang, C. Wang, T. Kang, P.G. Rychahou, Y.I. Chi, B.M. Evers, and B.P. Zhou. 2013. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene. 32:1351-1362. https ://doi. org /10. 1038 /onc. 2012. 169
11. Edgar, R., M. Domrachev, and A.E. Lash. 2002. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30:207-210. https ://doi. org /10. 1093 /nar /30. 1. 207
12. Fraga, M.F., E. Ballestar, A. Villar-Garea, M. Boix-Chornet, J. Espada, G. Schotta, T. Bonaldi, C. Haydon, S. Ropero, K. Petrie, et al. 2005. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37:391-400. https ://doi. org /10. 1038 /ng1531
13. Gao, J., B.A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S.O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, et al. 2013. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6:pl1. https ://doi. org /10. 1126 /scisignal. 2004088
14. Ghadban, T., J.L. Dibbern, M. Reeh, J.T. Miro, T.Y. Tsui, U. Wellner, J.R. Izbicki, C. Güngör, and Y.K. Vashist. 2017. HSP90 is a promising target in gemcitabine and 5-fluorouracil resistant pancreatic cancer. Apoptosis. 22:369-380. https ://doi. org /10. 1007 /s10495-016-1332-4
15. Ginnebaugh, K.R., A. Ahmad, and F.H. Sarkar. 2014. The therapeutic potential of targeting the epithelial-mesenchymal transition in cancer. Expert Opin. Ther. Targets. 18:731-745. https ://doi. org /10. 1517 /14728222. 2014. 909807
16. Gregoire, P., and J. Reeder. 2014. HTSeqGenie: A NGS analysis pipeline. package version 3.16.0
17. Hernandez, N. 1985. Formation of the 3' end of U1 snRNA is directed by a conserved sequence located downstream of the coding region. EMBO J. 4:1827-1837
18. Huang, P., C.Y. Wang, S.M. Gou, H.S. Wu, T. Liu, and J.X. Xiong. 2008. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J. Gastroenterol. 14:3903-3907. https ://doi. org /10. 3748 /wjg. 14. 3903
19. Jolly, M.K., M. Boareto, B. Huang, D. Jia, M. Lu, E. Ben-Jacob, J.N. Onuchic, and H. Levine. 2015. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front. Oncol. 5:155. https ://doi. org /10. 3389 / fonc. 2015. 00155
20. Jones, P.A., J.P. Issa, and S. Baylin. 2016. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17:630-641. https ://doi. org /10. 1038 /nrg. 2016. 93
21. Karachentsev, D., K. Sarma, D. Reinberg, and R. Steward. 2005. PR-Set7-dependent methylation of histone H4 Lys 20 functions in repression of gene expression and is essential for mitosis. Genes Dev. 19:431-435. https ://doi. org /10. 1101 /gad. 1263005
22. Klijn, C., S. Durinck, E.W. Stawiski, P.M. Haverty, Z. Jiang, H. Liu, J. Degenhardt, O. Mayba, F. Gnad, J. Liu, et al. 2015. A comprehensive transcriptional portrait of human cancer cell lines. Nat. Biotechnol. 33:306-312. https :// doi. org /10. 1038 /nbt. 3080
23. Kourmouli, N., P. Jeppesen, S. Mahadevhaiah, P. Burgoyne, R. Wu, D.M. Gilbert, S. Bongiorni, G. Prantera, L. Fanti, S. Pimpinelli, et al. 2004. Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J. Cell Sci. 117:2491-2501. https ://doi. org /10. 1242 /jcs. 01238
24. Kumar, P., G. Goh, S. Wongphayak, D. Moreau, and F. Bard. 2013. ScreenSifter: analysis and visualization of RNAi screening data. BMC Bioinformatics. 14:290. https ://doi. org /10. 1186 /1471-2105-14-290
25. Law, C.W., Y. Chen, W. Shi, and G.K. Smyth. 2014. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 15:R29. https ://doi. org /10. 1186 /gb-2014-15-2-r29
26. Lee, B., A. Villarreal-Ponce, M. Fallahi, J. Ovadia, P. Sun, Q.C. Yu, S. Ito, S. Sinha, Q. Nie, and X. Dai. 2014. Transcriptional mechanisms link epithelial plasticity to adhesion and differentiation of epidermal progenitor cells. Dev. Cell. 29:47-58. https ://doi. org /10. 1016 /j. devcel. 2014. 03. 005
27. Li, Y., D. Kong, A. Ahmad, B. Bao, and F.H. Sarkar. 2013. Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett. 338:94-100. https ://doi. org /10. 1016 /j. canlet. 2012. 03. 018
28. Li, Z., F. Nie, S. Wang, and L. Li. 2011. Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc. Natl. Acad. Sci. USA. 108:3116-3123. https ://doi. org /10. 1073 /pnas. 1009353108
29. Liberzon, A., A. Subramanian, R. Pinchback, H. Thorvaldsdóttir, P. Tamayo, and J.P. Mesirov. 2011. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 27:1739-1740. https ://doi. org /10. 1093 /bioinformatics /btr260
30. Liberzon, A., C. Birger, H. Thorvaldsdóttir, M. Ghandi, J.P. Mesirov, and P. Tamayo. 2015. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1:417-425. https ://doi. org /10. 1016 /j. cels. 2015. 12. 004
31. Lieber, M., J. Mazzetta, W. Nelson-Rees, M. Kaplan, and G. Todaro. 1975. Establishment of a continuous tumor-cell line (panc-1) from a human carcinoma of the exocrine pancreas. Int. J. Cancer. 15:741-747. https :// doi. org /10. 1002 /ijc. 2910150505
32. Lim, S., A. Janzer, A. Becker, A. Zimmer, R. Schüle, R. Buettner, and J. Kirfel. 2010. Lysine-specific demethylase 1 (LSD1) is highly expressed in ERnegative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 31:512-520. https ://doi. org /10. 1093 /carcin /bgp324
33. Lin, Y., Y. Wu, J. Li, C. Dong, X. Ye, Y.I. Chi, B.M. Evers, and B.P. Zhou. 2010. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 29:1803-1816. https ://doi. org /10. 1038 /emboj. 2010. 63
34. Lo, B., G. Strasser, M. Sagolla, C.D. Austin, M. Junttila, and I. Mellman. 2012. Lkb1 regulates organogenesis and early oncogenesis along AMPKdependent and-independent pathways. J. Cell Biol. 199:1117-1130. https ://doi. org /10. 1083 /jcb. 201208080
35. Maile, T.M., A. Izrael-Tomasevic, T. Cheung, G.D. Guler, C. Tindell, A. Masselot, J. Liang, F. Zhao, P. Trojer, M. Classon, and D. Arnott. 2015. Mass spectrometric quantification of histone post-translational modifications by a hybrid chemical labeling method. Mol. Cell. Proteomics. 14:1148-1158. https ://doi. org /10. 1074 /mcp. O114. 046573
36. Mani, S.A., W. Guo, M.J. Liao, E.N. Eaton, A. Ayyanan, A.Y. Zhou, M. Brooks, F. Reinhard, C.C. Zhang, M. Shipitsin, et al. 2008. The epithelialDownloaded mesenchymal transition generates cells with properties of stem cells. Cell. 133:704-715. https ://doi. org /10. 1016 /j. cell. 2008. 03. 027
37. Milne, T.A., K. Zhao, and J.L. Hess. 2009. Chromatin immunoprecipitation (ChIP) for analysis of histone modifications and chromatin-associated proteins. Methods Mol. Biol. 538:409-423. https ://doi. org /10. 1007 /978.-1-59745-418-6 21
38. Neve, R.M., K. Chin, J. Fridlyand, J. Yeh, F.L. Baehner, T. Fevr, L. Clark, N. Bayani, J.P. Coppe, F. Tong, et al. 2006. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 10:515-527. https ://doi. org /10. 1016 /j. ccr. 2006. 10. 008
39. Nieto, M.A. 2013. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 342:1234850. https ://doi. org /10. 1126 /science. 1234850
40. Pattabiraman, D.R., B. Bierie, K.I. Kober, P. Thiru, J.A. Krall, C. Zill, F. Reinhardt, W.L. Tam, and R.A. Weinberg. 2016. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science. 351:aad3680. https ://doi. org /10. 1126 /science. aad3680
41. Peinado, H., E. Ballestar, M. Esteller, and A. Cano. 2004. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell. Biol. 24:306-319. https ://doi. org /10. 1128 /MCB. 24. 1. 306-319. 2004
42. Peinado, H., M. Del Carmen Iglesias-de la Cruz, D. Olmeda, K. Csiszar, K.S. Fong, S. Vega, M.A. Nieto, A. Cano, and F. Portillo. 2005. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 24:3446-3458. https ://doi. org /10. 1038 /sj. emboj. 7600781
43. Rhim, A.D., E.T. Mirek, N.M. Aiello, A. Maitra, J.M. Bailey, F. McAllister, M. Reichert, G.L. Beatty, A.K. Rustgi, R.H. Vonderheide, et al. 2012. EMT and dissemination precede pancreatic tumor formation. Cell. 148:349-361. https ://doi. org /10. 1016 /j. cell. 2011. 11. 025
44. Roca, H., J. Hernandez, S. Weidner, R.C. McEachin, D. Fuller, S. Sud, T. Schumann, J.E. Wilkinson, A. Zaslavsky, H. Li, et al. 2013. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One. 8:e76773. https ://doi. org /10. 1371 /journal. pone. 0076773
45. Sayan, A.E., T.R. Griffiths, R. Pal, G.J. Browne, A. Ruddick, T. Yagci, R. Edwards, N.J. Mayer, H. Qazi, S. Goyal, et al. 2009. SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc. Natl. Acad. Sci. USA. 106:14884-14889. https ://doi. org /10. 1073 /pnas. 0902042106
46. Scheel, C., and R.A. Weinberg. 2012. Cancer stem cells and epithelialmesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22:396-403. https ://doi. org /10. 1016 /j. semcancer. 2012. 04. 001
47. Schotta, G., M. Lachner, K. Sarma, A. Ebert, R. Sengupta, G. Reuter, D. Reinberg, and T. Jenuwein. 2004. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18:1251-1262. https ://doi. org /10. 1101 /gad. 300704
48. Schotta, G., R. Sengupta, S. Kubicek, S. Malin, M. Kauer, E. Callén, A. Celeste, M. Pagani, S. Opravil, I.A. De La Rosa-Velazquez, et al. 2008. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 22:2048-2061. https ://doi. org /10. 1101 /gad. 476008
49. Shinchi, Y., M. Hieda, Y. Nishioka, A. Matsumoto, Y. Yokoyama, H. Kimura, S. Matsuura, and N. Matsuura. 2015. SUV420H2 suppresses breast cancer cell invasion through down regulation of the SH2 domaincontaining focal adhesion protein tensin-3. Exp. Cell Res. 334:90-99. https ://doi. org /10. 1016 /j. yexcr. 2015. 03. 010
50. Singh, A., and J. Settleman. 2010. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 29:4741-4751. https ://doi. org /10. 1038 /onc. 2010. 215
51. Singh, A., P. Greninger, D. Rhodes, L. Koopman, S. Violette, N. Bardeesy, and J. Settleman. 2009. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 15:489-500. https ://doi. org /10. 1016 /j. ccr. 2009. 03. 022
52. Song, Y., M.K. Washington, and H.C. Crawford. 2010. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res. 70:2115-2125. https ://doi. org /10. 1158 /0008-5472. CAN-09-2979
53. Srinivasan, K., B.A. Friedman, J.L. Larson, B.E. Lauffer, L.D. Goldstein, L.L. Appling, J. Borneo, C. Poon, T. Ho, F. Cai, et al. 2016. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7:11295. https ://doi. org /10. 1038 /ncomms11295
54. Talasz, H., H.H. Lindner, B. Sarg, and W. Helliger. 2005. Histone H4-lysine 20. monomethylation is increased in promoter and coding regions of active genes and correlates with hyperacetylation. J. Biol. Chem. 280:38814-38822. https ://doi. org /10. 1074 /jbc. M505563200
55. Tam, W.L., and R.A. Weinberg. 2013. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19:1438-1449. https ://doi. org /10. 1038 /nm. 3336
56. Thiery, J.P. 2003. Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15:740-746. https ://doi. org /10. 1016. /j. ceb. 2003. 10. 006
57. Thiery, J.P., H. Acloque, R.Y. Huang, and M.A. Nieto. 2009. Epithelialmesenchymal transitions in development and disease. Cell. 139:871-890. https ://doi. org /10. 1016 /j. cell. 2009. 11. 007
58. Tsai, J.H., and J. Yang. 2013. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 27:2192-2206. https ://doi. org /10. 1101 /gad. 225334. 113
59. Vinogradova, M., V.S. Gehling, A. Gustafson, S. Arora, C.A. Tindell, C. Wilson, K.E. Williamson, G.D. Guler, P. Gangurde, W. Manieri, et al. 2016. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 12:531-538. https ://doi. org /10. 1038 /nchembio. 2085
60. von Burstin, J., S. Eser, M.C. Paul, B. Seidler, M. Brandl, M. Messer, A. von Werder, A. Schmidt, J. Mages, P. Pagel, A. Schnieke, R.M. Schmid, G. Schneider, and D. Saur. 2009. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNA IL/HDAC1/HDAC2. repressor complex. Gastroenterology. 137:361-371
61. Warzecha, C.C., and R.P. Carstens. 2012. Complex changes in alternative premRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). Semin. Cancer Biol. 22:417-427. https ://doi. org /10. 1016 /j. semcancer. 2012. 04. 003
62. Wilson, C., K. Nicholes, D. Bustos, E. Lin, Q. Song, J.P. Stephan, D.S. Kirkpatrick, and J. Settleman. 2014. Overcoming EMT-associated resistance to anticancer drugs via Src/FAK pathway inhibition. Oncotarget. 5:7328-7341. https ://doi. org /10. 18632 /oncotarget. 2397
63. Wilson, C., X. Ye, T. Pham, E. Lin, S. Chan, E. McNamara, R.M. Neve, L. Belmont, H. Koeppen, R.L. Yauch, et al. 2014. AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res. 74:5878-5890. https ://doi. org /10. 1158 /0008-5472. CAN-14-1009
64. Witta, S.E., R.M. Gemmill, F.R. Hirsch, C.D. Coldren, K. Hedman, L. Ravdel, B. Helfrich, R. Dziadziuszko, D.C. Chan, M. Sugita, et al. 2006. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 66:944-950. https ://doi. org /10. 1158 /0008-5472. CAN-05-1988
65. Wu, D., and G.K. Smyth. 2012. Camera: a competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res. 40:e133. https ://doi. org /10. 1093 /nar /gks461
66. Wu, T.D., and S. Nacu. 2010. Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics. 26:873-881. https :// doi. org /10. 1093 /bioinformatics /btq057
67. Xiong, H.Q., K. Carr, and J.L. Abbruzzese. 2006. Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions. Drugs. 66:1059-1072. https ://doi. org /10. 2165 /00003495-200666080-00003
68. Yang, J., and R.A. Weinberg. 2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell. 14:818-829. https ://doi. org /10. 1016 /j. devcel. 2008. 05. 009
69. Yauch, R.L., T. Januario, D.A. Eberhard, G. Cavet, W. Zhu, L. Fu, T.Q. Pham, R. Soriano, J. Stinson, S. Seshagiri, et al. 2005. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin. Cancer Res. 11:8686-8698. https ://doi. org /10. 1158 /1078-0432. CCR-05-1492
70. Yin, T., H. Wei, S. Gou, P. Shi, Z. Yang, G. Zhao, and C. Wang. 2011. Cancer stem-like cells enriched in Panc-1 spheres possess increased migration ability and resistance to gemcitabine. Int. J. Mol. Sci. 12:1595-1604. https ://doi. org /10. 3390 /ijms12031595
71. Yokoyama, Y., A. Matsumoto, M. Hieda, Y. Shinchi, E. Ogihara, M. Hamada, Y. Nishioka, H. Kimura, K. Yoshidome, M. Tsujimoto, and N. Matsuura. 2014. Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. Breast Cancer Res. 16:R66. https ://doi. org /10. 1186 /bcr3681