The SIX1-EYA transcriptional complex as a therapeutic target in cancer

Expert Opinion on Therapeutic Targets

Volumn 19, Issue 2, 2015, Pages 213-225

  Blevins, Melanie A ^a   Towers, Christina G ^a   Patrick, Aaron N ^a   Zhao, Rui ^a   Ford, Heide L ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

Inhibition of transcriptional complexes; Metastasis; Phosphatase; Protein protein interaction; Six1 eyes absent complex; Transcription factor

Indexed keywords

PROTEIN TYROSINE PHOSPHATASE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR EYA; TRANSCRIPTION FACTOR SIX1; UNCLASSIFIED DRUG; EYA2 PROTEIN, HUMAN; HOMEODOMAIN PROTEIN; NUCLEAR PROTEIN; SIGNAL PEPTIDE; SIX1 PROTEIN, HUMAN;

CANCER INHIBITION; CARCINOGENESIS; COMPLEX FORMATION; DNA DAMAGE; ENZYME INHIBITION; GENETIC DISORDER; HUMAN; METASTASIS; NONHUMAN; PROTEIN FAMILY; PROTEIN PROTEIN INTERACTION; REVIEW; ADULT; ANIMAL; BREAST NEOPLASMS; DISEASE COURSE; FEMALE; GENE EXPRESSION REGULATION; GENETICS; MOLECULARLY TARGETED THERAPY; NEOPLASMS; PATHOLOGY;

ADULT; ANIMALS; BREAST NEOPLASMS; DISEASE PROGRESSION; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HOMEODOMAIN PROTEINS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MOLECULAR TARGETED THERAPY; NEOPLASM METASTASIS; NEOPLASMS; NUCLEAR PROTEINS; PROTEIN TYROSINE PHOSPHATASES;

EID: 84921284301     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2014.978860     Document Type: Review

References (115)

1. Kumar JP. The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell Mol Life Sci 2009;66(4):565-83
2. Xu PX. The EYA-SO/SIX complex in development and disease. Pediatr Nephrol 2012;28(6):843-54
3. Ford HL, Kabingu EN, Bump EA, et al. Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis. Proc Natl Acad Sci USA 1998;95(21):12608-13
4. Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 2003;426(6964):247-54
5. Coletta RD, Christensen K, Reichenberger KJ, et al. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Proc Natl Acad Sci USA 2004;101(17):6478-83
6. Li X, Perissi V, Liu F, et al. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science 2002;297(5584):1180-3
7. Del Bene F, Tessmar-Raible K, Wittbrodt J. Direct interaction of geminin and Six3 in eye development. Nature 2004;427(6976):745-9
8. El-Hashash AH, Al Alam D, Turcatel G, et al. Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 2011;353(2):242-58
9. Self M, Lagutin OV, Bowling B, et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J 2006;25(21):5214-28
10. Kobayashi H, Kawakami K, Asashima M, et al. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech Dev 2007;124(4):290-303
11. Abdelhak S, Kalatzis V, Heilig R, et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet 1997;15(2):157-64
12. Hoskins BE, Cramer CH, Silvius D, et al. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet 2007;80(4):800-4
13. Laclef C, Hamard G, Demignon J, et al. Altered myogenesis in Six1-deficient mice. Development 2003;130(10):2239-52
14. Laclef C, Souil E, Demignon J, et al. Thymus, kidney and craniofacial abnormalities in Six1 deficient mice. Mech Dev 2003;120(6):669-79
15. Xu PX, Zheng W, Huang L, et al. Six1 is required for the early organogenesis of mammalian kidney. Development 2003;130(14):3085-94
16. Zheng W, Huang L, Wei ZB, et al. The role of Six1 in mammalian auditory system development. Development 2003;130(17):3989-4000
17. Christensen KL, Patrick AN, McCoy EL, et al. The six family of homeobox genes in development and cancer. Adv Cancer Res 2008;101:93-126
18. Kawakami K, Sato S, Ozaki H, et al. Six family genes - structure and function as transcription factors and their roles in development. Bioessays 2000;22(7):616-26
19. Patrick AN, Cabrera JH, Smith AL, et al. Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol 2013;20(4):447-53
20. Kawakami K, Ohto H, Ikeda K, et al. Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development. Nucleic Acids Res 1996;24(2):303-10
21. Brodbeck S, Besenbeck B, Englert C. The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Mech Dev 2004;121(10):1211-22
22. Rebay I, Silver SJ, Tootle TL. New vision from Eyes absent: transcription factors as enzymes. Trends Genet 2005;21(3):163-71
23. Ohto H, Kamada S, Tago K, et al. Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya. Mol Cell Biol 1999;19(10):6815-24
24. Xu PX, Cheng J, Epstein JA, et al. Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function. Proc Natl Acad Sci USA 1997;94(22):11974-9
25. Okabe Y, Sano T, Nagata S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 2009;460(7254):520-4
26. Sano T, Nagata S. Characterization of the threonine-phosphatase of mouse eyes absent 3. FEBS Lett 2011;585(17):2714-19
27. Tadjuidje E, Hegde RS. The Eyes Absent proteins in development and disease. Cell Mol Life Sci 2013;70(11):1897-913
28. Tootle TL, Silver SJ, Davies EL, et al. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 2003;426(6964):299-302
29. Rayapureddi JP, Kattamuri C, Steinmetz BD, et al. Eyes absent represents a class of protein tyrosine phosphatases. Nature 2003;426(6964):295-8
30. Cook PJ, Ju BG, Telese F, et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 2009;458(7238):591-6
31. Krishnan N, Jeong DG, Jung SK, et al. Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent. J Biol Chem 2009;284(24):16066-70
32. Yuan B, Cheng L, Chiang HC, et al. A phosphotyrosine switch determines the antitumor activity of ERbeta. J Clin Invest 2014;124(8):3378-90
33. Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011;11(8):597-608
34. Nica G, Herzog W, Sonntag C, et al. Eya1 is required for lineage-specific differentiation, but not for cell survival in the zebrafish adenohypophysis. Dev Biol 2006;292(1):189-204
35. Xu PX, Adams J, Peters H, et al. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 1999;23(1):113-17
36. Zou D, Silvius D, Fritzsch B, et al. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development 2004;131(22):5561-72
37. Brugmann SA, Pandur PD, Kenyon KL, et al. Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor. Development 2004;131(23):5871-81
38. Ruf RG, Xu PX, Silvius D, et al. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci USA 2004;101(21):8090-5
39. Kozlowski DJ, Whitfield TT, Hukriede NA, et al. The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Dev Biol 2005;277(1):27-41
40. Bricaud O, Collazo A. The transcription factor six1 inhibits neuronal and promotes hair cell fate in the developing zebrafish (Danio rerio) inner ear. J Neurosci 2006;26(41):10438-51
41. Li Y, Manaligod JM, Weeks DL. EYA1 mutations associated with the branchio-oto-renal syndrome result in defective otic development in Xenopus laevis. Biol Cell 2010;102(5):277-92
42. Zou D, Silvius D, Rodrigo-Blomqvist S, et al. Eya1 regulates the growth of otic epithelium and interacts with Pax2 during the development of all sensory areas in the inner ear. Dev Biol 2006;298(2):430-41
43. Song MH, Kwon TJ, Kim HR, et al. Mutational analysis of EYA1, SIX1 and SIX5 genes and strategies for management of hearing loss in patients with BOR/BO syndrome. PLoS One 2013;8:6):e67236
44. Azuma N, Hirakiyama A, Inoue T, et al. Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Hum Mol Genet 2000;9(3):363-6
45. Orten DJ, Fischer SM, Sorensen JL, et al. Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Hum Mutat 2008;29(4):537-44
46. Patrick AN, Schiemann BJ, Yang K, et al. Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. J Biol Chem 2009;284(31):20781-90
47. Buller C, Xu X, Marquis V, et al. Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome. Hum Mol Genet 2001;10(24):2775-81
48. Rayapureddi JP, Hegde RS. Branchio-oto-renal syndrome associated mutations in Eyes Absent 1 result in loss of phosphatase activity. FEBS Lett 2006;580(16):3853-9
49. Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer 2002;2(10):777-85
50. Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 2004;10(2):175-81
51. Micalizzi DS, Christensen KL, Jedlicka P, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest 2009;119(9):2678-90
52. Ng KT, Man K, Sun CK, et al. Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma. Br J Cancer 2006;95(8):1050-5
53. Behbakht K, Qamar L, Aldridge CS, et al. Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res 2007;67(7):3036-42
54. Mimae T, Okada M, Hagiyama M, et al. Upregulation of notch2 and six1 is associated with progression of early-stage lung adenocarcinoma and a more aggressive phenotype at advanced stages. Clin Cancer Res 2012;18(4):945-55
55. Zheng XH, Liang PH, Guo JX, et al. Expression and clinical implications of homeobox gene Six1 in cervical cancer cell lines and cervical epithelial tissues. Int J Gynecol Cancer 2010;20(9):1587-92
56. Li Z, Tian T, Lv F, et al. Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PLoS One 2013;8(3):e59203
57. Yu Y, Davicioni E, Triche TJ, et al. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 2006;66(4):1982-9
58. Iwanaga R, Wang CA, Micalizzi DS, et al. Expression of Six1 in luminal breast cancers predicts poor prognosis and promotes increases in tumor initiating cells by activation of extracellular signal-regulated kinase and transforming growth factor-beta signaling pathways. Breast Cancer Res 2012;14(4):R100
59. McCoy EL, Iwanaga R, Jedlicka P, et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J Clin Invest 2009;119(9):2663-77
60. Wang CA, Jedlicka P, Patrick AN, et al. SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Invest 2012;122(5):1895-906
61. Ng KT, Lee TK, Cheng Q, et al. Suppression of tumorigenesis and metastasis of hepatocellular carcinoma by shRNA interference targeting on homeoprotein Six1. Int J Cancer 2010;127(4):859-72
62. Micalizzi DS, Wang CA, Farabaugh SM, et al. Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. Cancer Res 2010;70(24):10371-80
63. Coletta RD, Christensen KL, Micalizzi DS, et al. Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation. Cancer Res 2008;68(7):2204-13
64. Imam JS, Buddavarapu K, Lee-Chang JS, et al. MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers. Oncogene 2010;29(35):4971-9
65. Hua L, Fan L, Aichun W, et al. Inhibition of Six1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells. Tumour Biol 2014;35(3):1925-31
66. Li Z, Tian T, Hu X, et al. Six1 mediates resistance to paclitaxel in breast cancer cells. Biochem Biophys Res Commun 2013;441(3):538-43
67. Tan J, Zhang C, Qian J. Expression and significance of Six1 and Ezrin in cervical cancer tissue. Tumour Biol 2011;32(6):1241-7
68. Ono H, Imoto I, Kozaki K, et al. SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene 2012;31(47):4923-34
69. Zhao H, Xu Z, Qin H, et al. miR-30b regulates migration and invasion of human colorectal cancer via SIX1. Biochem J 2014;460(1):117-25
70. Li Z, Tian T, Hu X, et al. Targeting Six1 by lentivirus-mediated RNA interference inhibits colorectal cancer cell growth and invasion. Int J Clin Exp Pathol 2014;7(2):631-9
71. Reichenberger KJ, Coletta RD, Schulte AP, et al. Gene amplification is a mechanism of Six1 overexpression in breast cancer. Cancer Res 2005;65(7):2668-75
72. Li CM, Guo M, Borczuk A, et al. Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition. Am J Pathol 2002;160(6):2181-90
73. Robin TP, Smith A, McKinsey E, et al. EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Mol Cancer Res 2012;10(8):1098-108
74. Wang Y, Klijn JG, Zhang Y, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 2005;365(9460):671-9
75. Zhang L, Yang N, Huang J, et al. Transcriptional coactivator Drosophila eyes absent homologue 2 is up-regulated in epithelial ovarian cancer and promotes tumor growth. Cancer Res 2005;65(3):925-32
76. Guo JT, Ding LH, Liang CY, et al. [Expression of EYA2 in non-small cell lang cancer]. Zhonghua Zhong Liu Za Zhi 2009;31(7):528-31
77. Farabaugh SM, Micalizzi DS, Jedlicka P, et al. Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-beta signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene 2012;31(5):552-62
78. Zou H, Harrington JJ, Shire AM, et al. Highly methylated genes in colorectal neoplasia: implications for screening. Cancer Epidemiol Biomarkers Prev 2007;16(12):2686-96
79. Vincent A, Hong SM, Hu C, et al. Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth. Oncotarget 2014;5(9):2575-87
80. Gutierrez ML, Munoz-Bellvis L, Abad Mdel M, et al. Association between genetic subgroups of pancreatic ductal adenocarcinoma defined by high density 500 K SNP-arrays and tumor histopathology. PLoS One 2011;6(7):e22315
81. Wang QF, Wu G, Mi S, et al. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood 2011;117(25):6895-905
82. Clark SW, Fee BE, Cleveland JL. Misexpression of the eyes absent family triggers the apoptotic program. J Biol Chem 2002;277(5):3560-7
83. Wu K, Li Z, Cai S, et al. EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. Cancer Res 2013;73(14):4488-99
84. Pandey RN, Rani R, Yeo EJ, et al. The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells. Oncogene 2010;29(25):3715-22
85. Tadjuidje E, Wang TS, Pandey RN, et al. The EYA tyrosine phosphatase activity is pro-angiogenic and is inhibited by benzbromarone. PLoS One 2012;7(4):e34806
86. Auvergne RM, Sim FJ, Wang S, et al. Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes. Cell Rep 2013;3(6):2127-41
87. Yan C, Higgins PJ. Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta 2013;1835(1):76-85
88. Wu W, Ren Z, Li P, et al. Six1: A critical transcription factor in tumorigenesis. Int J Cancer 2014. [Epub ahead of print]
89. Nero TL, Morton CJ, Holien JK, et al. Oncogenic protein interfaces: small molecules, big challenges. Nat Rev Cancer 2014;14(4):248-62
90. Rudin CM, Hann CL, Garon EB, et al. Phase II study of singsle-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 2012;18(11):3163-9
91. Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008;68(9):3421-8
92. Ding Q, Zhang Z, Liu JJ, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 2013;56(14):5979-83
93. Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012;13(11):1133-40
94. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303(5659):844-8
95. Carry JC, Garcia-Echeverria C. Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic. Bioorg Med Chem Lett 2013;23(9):2480-5
96. Clackson T, Wells JA. A hot spot of binding energy in a hormone-receptor interface. Science 1995;267(5196):383-6
97. Grifone R, Laclef C, Spitz F, et al. Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype. Mol Cell Biol 2004;24(14):6253-67
98. Gordon BS, Delgado Diaz DC, White JP, et al. Six1 and Six1 cofactor expression is altered during early skeletal muscle overload in mice. J Physiol Sci 2012;62(5):393-401
99. Le Grand F, Grifone R, Mourikis P, et al. Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration. J Cell Biol 2012;198(5):815-32
100. Nord H, Nygard Skalman L, von Hofsten J. Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish. J Cell Sci 2013;126(Pt 8):1868-80
101. Liu Y, Chakroun I, Yang D, et al. Six1 regulates MyoD expression in adult muscle progenitor cells. PLoS One 2013;8(6):e67762
102. Delgado-Olguin P, Huang Y, Li X, et al. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 2012;44(3):343-7
103. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12(5):489-95
104. Jung SK, Jeong DG, Chung SJ, et al. Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor. FASEB J 2010;24(2):560-9
105. He R, Zeng LF, He Y, et al. Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J 2013;280(2):731-50
106. Pandey RN, Wang TS, Tadjuidje E, et al. Structure-activity relationships of benzbromarone metabolites and derivatives as EYA inhibitory antiangiogenic agents. PLoS One 2013;8(12):e84582
107. Park H, Jung SK, Yu KR, et al. Structure-based virtual screening approach to the discovery of novel inhibitors of eyes absent 2 phosphatase with various metal chelating moieties. Chem Biol Drug Des 2011;78(4):642-50
108. Park H, Ryu SE, Kim SJ. Structure-based de novo design of Eya2 phosphatase inhibitors. J Mol Graph Model 2012;38:382-8
109. Krueger AB, Dehdashti SJ, Southall N, et al. Identification of a selective smallmolecule inhibitor series targeting the eyes absent 2 (Eya2) phosphatase activity. J Biomol Screen 2013;18(1):85-96
110. Krueger AB, Drasin DJ, Lea WA, et al. Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated migration. J Biol Chem 2014;289(23):16349-61
111. van Westen GJ, Gaulton A, Overington JP. Chemical, target, and bioactive properties of allosteric modulation. PLoS Comput Biol 2014;10(4):e1003559
112. Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat Rev Cancer 2002;2(10):740-9
113. Ostman A, Hellberg C, Bohmer FD. Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 2006;6(4):307-20
114. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 2010;53(7):2719-40
115. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74