DISCOVERIES (ISSN 2359-7232), 2018, October-December issue

CITATION: 

Submitted: December 17; Revised: December 31st, 2018; Accepted: December 31st, 2018; Published: December 31st, 2018; 

 GO BACK to 2018, October-December issue

 GO BACK to DISCOVERIES

The Curious Case of ZEB1

Mecca Madany (1), Tom Thomas (2), Lincoln A. Edwards (3, *)

(1) Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA;
(2) Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School Boston, MA, USA;
(3) Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA;

*Corresponding author: Lincoln A. Edwards, PhD, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 413 E 69th St, New York, NY, USA; Email: lae2011@med.cornell.edu

Abstract

The Zinc Finger E-box binding homeobox (ZEB1/TCF8 or DeltaEF1) is at the forefront of transcription factors involved in controlling epithelial-to-mesenchymal transitions (EMT). Essentially, EMT allows for the reorganization of epithelial cells to become migratory cells with a mesenchymal phenotype.  In addition to ZEB1 being involved in embryonic development, ZEB1 has also been linked to processes involving micro-RNAs, long non-coding RNAs and stem cells. In recent years there has been an accumulation of evidence with regard to ZEB1 in various cancers. Although increased ZEB1 expression has largely been associated with EMT, cancer invasion, and tumorigenicity, there have been some episodic reports that have gone against the traditional reporting of the role of ZEB1. Indicating that the function of ZEB1 and the mechanisms by which ZEB1 facilitates its activities is more complex than was once appreciated. This complexity is further exacerbated by the notion that ZEB1 can act not only as a transcriptional repressor but a transcriptional activator as well. This review seeks to shed light on the complexity of ZEB1 with respect to cancer.

Access full text of the manuscript here: Full text (pdf)

References

1. Hay ED. An overview of epithelia-mesenchymal transformation. Acta Anat (Basel). 1995; 154:8-20.
2. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7:131-42.
3. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139:871-890.
4. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. JCI. 2009; 119:1420-1428.
5. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013; 13:97-110.
6. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15:178-196.
7. Zhang J, Ma L. MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev. 2012; 31:653-662.
8. Krebs AM, Mitschke J, Losada ML, Schmalhofer O, Boerries M, Busch H, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017; 19(5):518-529.
9. Zhang X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015; 527(7579):525-530.
10. Browne G, Sayan AE, Tulchinsky E. ZEB proteins link cell motility with cell cycle control and cell survival in cancer. Cell Cycle. 2010; 9(5):886-891.
11. Miyoshi T, Maruhashi M, Van De Putte T, Kondoh H, Huylebroeck D, Higashi Y, et al. Complementary expression pattern of Zfhx1 genes Sip1 and δEF1 in the mouse embryo and their genetic interaction revealed by compound mutants. Dev Dyn. 2006; 235:1941-1952.
12. Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G, Wierinckx A, et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell. 2013; 24:466-480.
13. Ye X, Brabletz T, Kang Y, Longmore GD, Nieto MA, Stanger BZ, et al. Upholding a role for EMT in breast cancer metastasis. Nature. 2017; 547:E1-E3.
14. Postigo, AA. Opposing functions of zeb proteins in the regulation of the tgfbeta/bmp signaling pathway. EMBO J. 2003; 22:2443–2452.
15. Funahashi J, Sekido R, Murai K, Kamachi Y, Kondoh H. Delta-crystallin enhancer binding protein delta EF1 is a zinc finger-homeodomain protein implicated in postgastrulation embryogenesis. Development. 1993; 119:433-46.
16. Takagi T, Moribe H, Kondoh H, Higashi, Y. DeltaEF1, a zinc finger and homeodomain transcription factor, is required for skeleton patterning in multiple lineages. Development. 1998; 125:21–31.
17. Postigo AA, Dean DC. ZEB represses transcription through interaction with the corepressor CtBP. PNAS. 1996a; 6683-6688.
18. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, et al. Deltaef1 is a transcriptional repressor of e-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005; 24:2375–2385.
19. Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, et al.  Zeb1 represses e-cadherin and induces an emt by recruiting the swi/snf chromatin remodeling protein brg1. Oncogene. 2010; 29:3490–3500.
20. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007; 7:415-28.
21. Williams TM, Moolten D, Burlein J, Romano J, Bhaerman R, Godillot A, et al. Identification of a zinc finger protein that inhibits IL-2 gene expression. Science. 1991; 254:1791-1794.
22. Fontemaggi G, Gurtner A, Strano S, Higashi Y, Sacchi A, Piaggio G, et al. The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation. Mol. Cell. Biol. 2001; 21:8461–8470.
23. Postigo AA, Dean DC. Independent repressor domains in ZEB regulate muscle and T-cell differentiation. Mol. Cell. Biol. 1999b; 19:7961-7971.
24. Spoelstra NS, Manning NG, Higashi Y, Darling D, Singh M, Shroyer KR, et al. The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res. 2006; 66:3893-902.
25. Bronsert P, Kohler I, Timme S, Kiefer S, Werner M, Schilling O, et al. Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery. 2014; 156:97-108.
26. Zhang GJ, Zhou T, Tian HP, Liu ZL, Xia SS. High expression of ZEB1 correlates with liver metastasis and poor prognosis in colorectal cancer. Oncol Lett. 2013; 5:564-8.
27. Okugawa Y, Toiyama Y, Tanaka K, Matsusita K, Fujikawa H, Saigusa S, et al. Clinical significance of Zinc finger E-box Binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol. 2012; 106(3):280-285.
28. Jia B, Liu H, Kong Q, Li B. Overexpression of ZEB1 associated with metastasis and invasion in patients with gastric carcinoma. Mol Cell Biochem. 2012; 366:223-9.
29. Zhang J, Lu C, Kang J, Cao C, Li M. Involvement of ZEB1 and E-cadherin in the invasion of lung squamous cell carcinoma. Mol Biol Rep. 2013; 40:949-56.
30. Yabusaki N, Yamada S, Murai T, Kanda M, Kobayashi D, Tanaka C, et al. Clinical significance of zinc finger E-box binding homeobox 1 mRNA levels in peritoneal washing for gastric cancer. Mol Clin Oncol. 2015; 3(2):435-441.
31. Okegawa T, Li Y, Pong RC, Hsieh JT. Cell adhesion proteins as tumor suppressors. J Urol. 2002; 167:1836 43.
32. Bae G-Y, So-Jung C, Ji-Seon L, Jisuk J, Jinseon L, Kim J, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013; 4(12): 2512-2522.
33. Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 2007; 26:6979-6988.
34. Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 2008; 68:537-544.
35. Sanchez-Tillo, E, Fanlo L, Siles L, Montes-Moreno S, Moros A, Chiva-Blanch G, et al. The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma. Cell death and diff.  2014; 21(2) 247-257.
36. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008; 9:582–589.
37. Hidaka T, Nakahata S, Hatakeyama K, Hamasaki M, Yamashita K, Kohno T, et al. Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma. Blood. 2008; 112(2):383-393.
38. Edwards LA, Fine HA. The Ids have it. Cancer Cell. 2010; 18(6):543-545.
39. Johnson, David G. The paradox of E2F1: oncogene and tumor suppressor gene. Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center 27.3 (2000): 151-157.

40. Manfredi, James J. The Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes & Dev. 2010; 24(15):1580-1589.
41. Drake JM, Barnes JM, Madsen JM, Domann FE, Stipp, CS, Henry MD, et al. ZEB1 coordinately regulates laminin-332 and β4 integrin expression altering the invasive phenotype of prostate cancer cells. JBC. 2010; 285(44):33940-33948.
42. Zhang T, Guo L, Creighton CJ, Lu Q, Gibbons DL, Yi ES, et al. A genetic cell context-dependent role for ZEB1 in lung cancer. Nature Comm. 2016;  7:12231.
43. Siebzehnrubl FA, Silver DJ, Tugertimur B, Deleyrolle LP, Siebzehnrubl D, et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Mol Med. 2013; 5:1196–1212.
44. Kahlert UD, Suwala AK, Raabe EH, Siebzehnrubl FA, Suarez MJ, Orr BA, et al. ZEB1 promotes invasion in human fetal neural stem cells and hypoxic glioma neurospheres. Brain pathology. 2015; 25(6): 724-732.
45. Suzuki K, Kawataki T, Endo K, Miyazawa K, Kinouchi H, Saitoh M. Expression of ZEBs in gliomas is associated with invasive properties and histopathological grade. Oncology letters. 2018; 16(2):1758-1764.
46. Rosmaninho P, Mukusch S, Piscopo V, Teixeira V, Raposo AA, Warta R, et al. Zeb1 potentiates genome‐wide gene transcription with Lef1 to promote glioblastoma cell invasion. EMBO J. 2018; 37(15):e97115.
47. Wang H, Zhao S, Chen B, Fu C, Dang Y, Fang P, et al. Repression of the expression of PPP3CC by ZEB1 confers activation of NF-κB and contributes to invasion and growth in glioma cells. Japanese journal of clinical oncology. 2017; 48(2):175-183.
48. Chen B, Lei Y, Wang H, Dang Y, Fang P, Wang J, et al. Repression of the expression of TET2 by ZEB1 contributes to invasion and growth in glioma cells. Molecular medicine reports. 2017; 15(5):2625-2632.
49. Nesvick CL, Zhang C, Edwards NA, Montgomery BK, Lee M, Yang C, et al. ZEB1 expression is increased in IDH1-mutant lower-grade gliomas. J Neurooncol. 2016; 130(1):111-122.

50. Huang X, Harrison X, Bai Y, Li Y. ZEB1 expression in Chinese lower-grade gliomas. Journal of neuro-oncology. 2017; 133(1):213-215.

51. Edwards LA, Li A, Berel D, Madany M, Kim NH, Liu M, et al. ZEB1 regulates glioma stemness through LIF repression. Sci Reports. 2017; 7(1): 69-81.
52. Morel A-P, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PloS one. 2008; 3(8):e2888.
53. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-715.
54.Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumor initiating cells. Nature. 2004; 432(7015):396-401.
55. Lee, J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. 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. 2006; 9(5):391-403.
56. Bao S, Wu Q, McLendon RE, Hao Y, Hjelmeland AB, Dewhirst MW, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-760.
57. Euskirchen P, Radke J, Schmidt MS, Schulze Heuling E, Kadikowski E, Maricos M, et al. Cellular heterogeneity contributes to subtype-specific expression of ZEB1 in human glioblastoma. PLoS One. 2017;12(9): e0185376.