CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Nature Reviews Cancer

Volumn 14, Issue 10, 2014, Pages 673-682

  Ramdzan, Zubaidah M ^a   Nepveu, Alain ^a,b  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ADVANCED CANCER; ALLELE; CANCER GENETICS; CANCER TISSUE; CARCINOGENESIS; CARCINOGENICITY; CELL FUNCTION; CUT LIKE HOMEOBOX 1 GENE; EXCISION REPAIR; GENE FUNCTION; GENE INACTIVATION; GENE OVEREXPRESSION; GENE REPRESSION; GENE TARGETING; GENETIC ASSOCIATION; HAPLOINSUFFICIENCY; HUMAN; IN VIVO STUDY; KNOCKOUT MOUSE; MOLECULAR BIOLOGY; NONHUMAN; ONCOGENE; POINT MUTATION; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION INITIATION; TRANSGENIC MOUSE; TUMOR GROWTH; TUMOR SUPPRESSOR GENE; TUMOR VOLUME; ANIMAL; COPY NUMBER VARIATION; GENE EXPRESSION; GENETIC PREDISPOSITION; GENETICS; METABOLISM; MUTATION; NEOPLASM; PATHOLOGY;

CUX1 PROTEIN, HUMAN; HOMEODOMAIN PROTEIN; NUCLEAR PROTEIN; REPRESSOR PROTEIN;

ANIMALS; CARCINOGENESIS; DNA COPY NUMBER VARIATIONS; GENE EXPRESSION; GENES, TUMOR SUPPRESSOR; GENETIC PREDISPOSITION TO DISEASE; HAPLOINSUFFICIENCY; HOMEODOMAIN PROTEINS; HUMANS; MUTATION; NEOPLASMS; NUCLEAR PROTEINS; REPRESSOR PROTEINS;

EID: 84910020859     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3805     Document Type: Review

References (85)

1. Blochlinger, K., Bodmer, R., Jack, J., Jan, L. Y., & Jan, Y. N. Primary structure and expression of a product from cut, a locus involved in specifying sensory organ identity in Drosophila. Nature 333, 629-635 (1988
2. Neufeld, E. J., Skalnik, D. G., Lievens, P. M., & Orkin, S. H. Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut. Nature Genet. 1, 50-55 (1992
3. Schoenmakers, E. F. et al. Identification of CUX1 as the recurrent chromosomal band 7q22 target gene in human uterine leiomyoma. Genes Chromosomes Cancer 52, 11-23 (2013
4. Jerez, A. et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 119, 6109-6117 (2012
5. McNerney, M. E. et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood 121, 975-983 (2013
6. Klampfl, T. et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood 118, 167-176 (2011
7. Hindersin, S., Niemeyer, C. M., Germing, U., Göbel, U., & Kratz, C. P. Mutation analysis of CUTL1 in childhood myeloid neoplasias with monosomy Leukemia Res. 31, 1323-1324 (2007
8. Patrikis, M. et al. Mutation analysis of CDP, TP53, and KRAS in uterine leiomyomas. Mol. Carcinogen. 37, 61-64 (2003
9. Moon, N. S. et al. Expression of N-terminally truncated isoforms of CDP/CUX is increased in human uterine leiomyomas. Int. J. Cancer 100, 429-432 (2002
10. Thoennissen, N. H. et al. Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood 115, 2882-2890 (2010
11. Wong, C. C. et al. Inactivating CUX1 mutations promote tumorigenesis. Nature Genet. 46, 33-38 (2014
12. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-337 (2012
13. Michl, P. et al. CUTL1 is a target of TGF? signaling that enhances cancer cell motility and invasiveness. Cancer Cell 7, 521-532 (2005
14. Ripka, S. et al. CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut 59, 1101-1110 (2010
15. Ledford, A. W. et al. Deregulated expression of the homeobox gene Cux-1 in transgenic mice results in downregulation of p27kip1 expression during nephrogenesis, glomerular abnormalities, and multiorgan hyperplasia. Dev. Biol. 245, 157-171 (2002
16. Cadieux, C. et al. Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia. Cancer Res. 66, 9492-9501 (2006
17. Cadieux, C. et al. Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types. Cancer Res. 69, 7188-7197 (2009
18. Ramdzan, Z. M. et al. RAS transformation requires CUX1-dependent repair of oxidative DNA damage. PLoS Biol. 12, e1001807 (2014
19. Sansregret, L. et al. Cut homeobox 1 causes chromosomal instability by promoting bipolar division after cytokinesis failure. Proc. Natl Acad. Sci. USA 108, 1949-1954 (2011
20. Siam, R. et al. Transcriptional activation of the Lats1 tumor suppressor gene in tumors of CUX1 transgenic mice. Mol. Cancer 8, 60-70 (2009
21. Sansregret, L. et al. The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase. Mol. Cell. Biol. 26, 2441-2455 (2006
22. Truscott, M. et al. Carboxyl-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells. J. Biol. Chem. 282, 30216-30226 (2007
23. Vadnais, C. et al. CUX1 transcription factor is required for optimal ATM/ATR-mediated responses to DNA damage. Nucleic Acids Res. 40, 4483-4495 (2012
24. Goulet, B. et al. Characterization of a tissue-specific CDP/Cux isoform, 75, activated in breast tumor cells. Cancer Res. 62, 6625-6633 (2002
25. Moon, N. S. et al. S Phase-specific proteolytic cleavage is required to activate stable DNA binding by the CDP/Cut homeodomain protein. Mol. Cell. Biol. 21, 6332-6345 (2001
26. Vanden Heuvel, G. B., Quaggin, S. E., & Igarashi, P. A. Unique variant of a homeobox gene related to Drosophila Cut is expressed in mouse testis. Biol. Reprod. 55, 731-739 (1996
27. Maitra, U., Seo, J., Lozano, M. M., & Dudley, J. P. Differentiation-induced cleavage of Cutl1/CDP generates a novel dominant-negative isoform that regulates mammary gene expression. Mol. Cell. Biol. 26, 7466-7478 (2006
28. Sansregret, L., & Nepveu, A. The multiple roles of CUX1: Insights from mouse models and cell-based assays. Gene 412, 84-94 (2008
29. Skalnik, D. G., Strauss, E. C., & Orkin, S. H. CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter. J. Biol. Chem. 266, 16736-16744 (1991
30. Lievens, P. M. J., Donady, J. J., Tufarelli, C., & Neufeld, E. J. Repressor activity of CCAAT displacement protein in HL-60 myeloid leukemia cells. J. Biol. Chem. 270, 12745-12750 (1995
31. Superti-Furga, G., Barberis, A., Schreiber, E., & Busslinger, M. The protein CDP, but not CP1, Footprints on the CCAAT region of the g-globulin gene in unfractionated B-cell extracts. Biochim. Biophys. Acta 1007, 237-242 (1989
32. Stunkel, W., Huang, Z., Tan, S. H., O'Connor, M. J., & Bernard, H. U. Nuclear matrix attachment regions of human papillomavirus type 16 repress or activate the E6 promoter, depending on the physical state of the viral DNA. J. Virol. 74, 2489-2501 (2000
33. Pattison, S., Skalnik, D. G., & Roman, A. Ccaat Displacement protein, a regulator of differentiation-specific gene expression, binds a negative regulatory element within the 5' end of the human papillomavirus type 6 long control region. J. Virol. 71, 2013-2022 (1997
34. Cubelos, B. et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron 66, 523-535 (2010
35. Ellis, T. et al. The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle. Genes Dev. 15, 2307-2319 (2001
36. Moon, N. S., Berube, G., & Nepveu, A. CCAAT displacement activity involves Cut repeats 1 and 2, not the Cut homeodomain. J. Biol. Chem. 275, 31325-31334 (2000
37. Mailly, F. et al. The human cut homeodomain protein can repress gene expression by two distinct mechanisms: active repression and competition for binding site occupancy. Mol. Cell. Biol. 16, 5346-5357 (1996
38. Dianov, G. L., & Hubscher, U. Mammalian base excision repair: the forgotten archangel. Nucleic Acids Res. 41, 3483-3490 (2013
39. Vadnais, C. et al. Long-range transcriptional regulation by the p110 CUX1 homeodomain protein on the ENCODE array. BMC Genomics 14, 258 (2013
40. Goulet, B. et al. A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S Phase and processes the CDP/Cux transcription factor. Mol. Cell 14, 207-219 (2004
41. Harada, R. et al. Genome-wide location analysis and expression studies reveal a role for p110 CUX1 in the activation of DNA replication genes. Nucleic Acids Res. 36, 189-202 (2008
42. Kedinger, V. et al. p110 CUX1 homeodomain protein stimulates cell migration and invasion in part through a regulatory cascade culminating in the repression of E-cadherin and occludin. J. Biol. Chem. 284, 27701-27711 (2009
43. Kuhnemuth, B. et al. CUX1 modulates polarization of tumor-Associated macrophages by antagonizing NF-?B signaling. Oncogene http://dx.doi.org/10.1038/onc.2013.530 (2013
44. Ozisik, Y. Y., Meloni, A. M., Surti, U., & Sandberg, A. A. Deletion 7q22 in uterine leiomyoma. A cytogenetic review. Cancer Genet. Cytogenet. 71, 1-6 (1993
45. Zeng, W. R. et al. Loss of heterozygosity and reduced expression of the CUTL1 gene in uterine leiomyomas. Oncogene 14, 2355-2365 (1997
46. Zeng, W. R. et al. Refined mapping of the region of loss of heterozygosity on the long arm of chromosome 7 in human breast cancer defines the location of a second tumor suppressor gene at 7q22 in the region of the CUTL1 gene. Oncogene 18, 2015-2021 (1999
47. Pedersen-Bjergaard, J., Andersen, M. T., & Andersen, M. K. Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Hematology Am. Soc. Hematol. Educ.Program 392-397 (2007
48. Zhang, Y., & Rowley, J. D. Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair 5, 1282-1297 (2006
49. Thoennissen, N. H. et al. Novel CUX1 missense mutation in association with 7q-At leukemic transformation of MPN. Am. J. Hematol. 86, 703-705 (2011
50. Luong, M. X. et al. Genetic ablation of the CDP/Cux protein C terminus results in hair cycle defects and reduced male fertility. Mol. Cell. Biol. 22, 1424-1437 (2002
51. Sinclair, A. M. et al. Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice. Blood 98, 3658-3667 (2001
52. Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature Methods 7, 248-249 (2010
53. Kumar, P., Henikoff, S., & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature Protoc. 4, 1073-1081 (2009
54. Collier, L. S., Carlson, C. M., Ravimohan, S., Dupuy, A. J., & Largaespada, D. A. Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436, 272-276 (2005
55. Glosli, H. et al. Effects of hTNF? expression in T cells on haematopoiesis in transgenic mice. Eur. J. Haematol. 63, 50-60 (1999
56. Lievens, P. M., Tufarelli, C., Donady, J. J., Stagg, A., & Neufeld, E. J. CASP, a novel, highly conserved alternative-splicing product of the CDP/cut/cux gene, lacks cut-repeat and homeo DNA-binding domains, and interacts with full-length CDP in vitro. Gene 197, 73-81 (1997
57. Gillingham, A. K., Pfeifer, A. C., & Munro, S. CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin. Mol. Biol. Cell 13, 3761-3774 (2002
58. Ripka, S. et al. WNT5A-target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 28, 1178-1187 (2007
59. Brantley, J. G., Sharma, M., Alcalay, N. I., & Heuvel, G. B. V. Cux-1 transgenic mice develop glomerulosclerosis and interstitial fibrosis. Kidney Int. 63, 1240-1248 (2003
60. Vanden Heuvel, G. B. et al. Hepatomegaly in transgenic mice expressing the homeobox gene Cux-1. Mol. Carcinog. 43, 18-30 (2005
61. Cadieux, C. et al. Polycystic kidneys caused by sustained expression of Cux1 isoform p75. J. Biol. Chem. 283, 13817-13824 (2008
62. Truscott, M. Harada, R., Vadnais, C., Robert, F., & Nepveu, A. p110 CUX1 cooperates with E2F transcription factors in the transcriptional activation of cell cycle-regulated genes. Mol. Cell. Biol. 28, 3127-3138 (2008
63. Seguin, L. et al. CUX1 and E2F1 regulate coordinated expression of the mitotic complex genes Ect2, MgcRacGAP, and MKLP1 in S phase. Mol. Cell. Biol. 29, 570-581 (2009
64. Aleksic, T. et al. CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation. Oncogene 26, 5939-5949 (2007
65. Kedinger, V., & Nepveu, A. The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion. Cell Adh. Migr. 4, 348-352 (2010
66. Michl, P., & Downward, J. CUTL1: a key mediator of TGF?-induced tumor invasion. Cell Cycle 5, 132-134 (2006
67. Hulea, L., & Nepveu, A. CUX1 transcription factors: from biochemical activities and cell-based assays to mouse models and human diseases. Gene 497, 18-26 (2012
68. van Wijnen, A. J., Wright, K. L., Lian, J. B., Stein, J. L., & Stein, G. S. Human H4 histone gene transcription requires the proliferation-specific nuclear factor HiNF-D. Auxiliary roles for HiNF-C (Sp1-like) and HiNF-A (high mobility group-like). J. Biol. Chem. 264, 15034-15042 (1989
69. Holthuis, J. et al. Tumor cells exhibit deregulation of the cell cycle histone gene promoter factor HiNF-D. Science 247, 1454-1457 (1990
70. van Wijnen, A. J. et al. CDP/cut is the DNA-binding subunit of histone gene transcription factor HiNF-D: a mechanism for gene regulation at the G1/S phase cell cycle transition point independent of transcription factor E2F. Proc. Natl Acad. Sci. USA 93,11516-11521 (1996
71. Truscott, M. et al. CDP/Cux stimulates transcription from the DNA polymerase ? gene promoter. Mol. Cell. Biol. 23, 3013-3028 (2003
72. Coqueret, O., Berube, G., & Nepveu, A. The mammalian Cut homeodomain protein functions as a cell-cycle-dependent transcriptional repressor which downmodulates p21WAF1/CIP1/SDI1 in S phase. EMBO J. 17, 4680-4694 (1998
73. Sharma, M., Fopma, A., Brantley, J. G., & Vanden Heuvel, G. B. Coexpression of Cux-1 and Notch signaling pathway components during kidney development. Dev. Dyn. 231, 828-838 (2004
74. Sharma, M. et al. Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice. Kidney Int. 67, 432-442 (2005
75. Sharma, M. et al. The homeodomain protein Cux1 interacts with Grg4 to repress p27 kip1 expression during kidney development. Gene 439, 87-94 (2009
76. He, X. et al. PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma. Cancer Res. 68, 5591-5598 (2008
77. Luo, J., Solimini, N. L., & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823-837 (2009
78. Silkworth, W. T., Nardi, I. K., Scholl, L. M., & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-Attachment and chromosome mis-segregation in cancer cells. PLoS ONE 4, e6564 (2009
79. Ganem, N. J., Godinho, S. A., & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278-282 (2009
80. Nigg, E. A. Centrosome aberrations: cause or consequence of cancer progression? Nature Rev. Cancer 2, 815-825 (2002
81. Storchova, Z., & Kuffer, C. The consequences of tetraploidy and aneuploidy. J. Cell Sci. 121, 3859-3866 (2008
82. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New Engl. J. Med. 366, 883-892 (2012
83. Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835-848 (2009
84. Curtin, N. J. DNA repair dysregulation from cancer driver to therapeutic target. Nature Rev. Cancer 12, 801-817 (2012
85. Shaheen, M., Allen, C., Nickoloff, J. A., & Hromas, R. Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117, 6074-6082 (2011).