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Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

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Abstract

The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis, and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions, or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

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References

  1. Cheng, Y. W., et al. (2008). CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clinical Cancer Research, 14(19), 6005–6013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Issa, J. P. (2008). Colon cancer: it's CIN or CIMP. Clinical Cancer Research, 14(19), 5939–5940.

    Article  PubMed  Google Scholar 

  3. Samowitz, W. S., et al. (2007). APC mutations and other genetic and epigenetic changes in colon cancer. Molecular Cancer Research, 5(2), 165–170.

    Article  CAS  PubMed  Google Scholar 

  4. Shen, L., et al. (2007). Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 104(47), 18654–18659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mirabelli-Primdahl, L., et al. (1999). Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Research, 59(14), 3346–3351.

    CAS  PubMed  Google Scholar 

  6. Akiyama, Y., et al. (1997). Transforming growth factor beta type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. Gastroenterology, 112(1), 33–39.

    Article  CAS  PubMed  Google Scholar 

  7. Calin, G. A., et al. (2000). Genetic progression in microsatellite instability high (MSI-H) colon cancers correlates with clinico-pathological parameters: a study of the TGRbetaRII, BAX, hMSH3, hMSH6, IGFIIR and BLM genes. International Journal of Cancer, 89(3), 230–235.

    Article  CAS  PubMed  Google Scholar 

  8. Peltomaki, P. (2005). Lynch syndrome genes. Familial Cancer, 4(3), 227–232.

    Article  PubMed  CAS  Google Scholar 

  9. Deng, G., et al. (2004). BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clinical Cancer Research, 10(1 Pt 1), 191–195.

    Article  CAS  PubMed  Google Scholar 

  10. Howlader, N., Noone, A. M., Krapcho, M., Miller, D., Bishop, K., Altekruse, S. F., Kosary, C. L., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D. R., Chen, H. S., Feuer, E. J., & Cronin, K. A. (Eds.). (2016). SEER cancer statistics review, 1975–2013. Bethesda: National Cancer Institute.

    Google Scholar 

  11. Jen, J., et al. (1994). Molecular determinants of dysplasia in colorectal lesions. Cancer Research, 54(21), 5523–5526.

    CAS  PubMed  Google Scholar 

  12. Stein, U., et al. (2009). MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nature Medicine, 15(1), 59–67.

    Article  CAS  PubMed  Google Scholar 

  13. Linardou, H., et al. (2008). Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. The Lancet Oncology, 9(10), 962–972.

    Article  CAS  PubMed  Google Scholar 

  14. The Cancer Genome Atlas Network. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487(7407), 330–337.

  15. Powell, S. M., et al. (1992). APC mutations occur early during colorectal tumorigenesis. Nature, 359(6392), 235–237.

    Article  CAS  PubMed  Google Scholar 

  16. Miyoshi, Y., et al. (1992). Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Human Molecular Genetics, 1(4), 229–233.

    Article  CAS  PubMed  Google Scholar 

  17. Groden, J., et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell, 66(3), 589–600.

    Article  CAS  PubMed  Google Scholar 

  18. Nishisho, I., et al. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science, 253(5020), 665–669.

    Article  CAS  PubMed  Google Scholar 

  19. Joslyn, G., et al. (1991). Identification of deletion mutations and three new genes at the familial polyposis locus. Cell, 66(3), 601–613.

    Article  CAS  PubMed  Google Scholar 

  20. Kinzler, K. W., et al. (1991). Identification of FAP locus genes from chromosome 5q21. Science, 253(5020), 661–665.

    Article  CAS  PubMed  Google Scholar 

  21. Giardiello, F. (1995). Gastrointestinal polyposis syndromes and hereditary nonpolyposis colorectal cancer. In A. K. Rustgi (Ed.), Gastrointestinal cancers: biology, diagnosis, and therapy (pp. 367–377). Philadelphia: Lippincott-Raven.

    Google Scholar 

  22. Ichii, S., et al. (1993). Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). Oncogene, 8(9), 2399–2405.

    CAS  PubMed  Google Scholar 

  23. Levy, D. B., et al. (1994). Inactivation of both APC alleles in human and mouse tumors. Cancer Research, 54(22), 5953–5958.

    CAS  PubMed  Google Scholar 

  24. Luongo, C., et al. (1994). Loss of Apc+ in intestinal adenomas from Min mice. Cancer Research, 54(22), 5947–5952.

    CAS  PubMed  Google Scholar 

  25. Conlin, A., et al. (2005). The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma. Gut, 54(9), 1283–1286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. van den Broek, E., et al. (2016). Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients. Oncotarget, 7(45), 73876–73887.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Samowitz, W. S., et al. (1999). β-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Research, 59(7), 1442–1444.

    CAS  PubMed  Google Scholar 

  28. Sparks, A. B., et al. (1998). Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer. Cancer Research, 58(6), 1130–1134.

    CAS  PubMed  Google Scholar 

  29. Morin, P. J., et al. (1997). Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 275(5307), 1787–1790.

    Article  CAS  PubMed  Google Scholar 

  30. Orford, K., et al. (1997). Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. The Journal of Biological Chemistry, 272(40), 24735–24738.

    Article  CAS  PubMed  Google Scholar 

  31. Behrens, J., et al. (1998). Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science, 280(5363), 596–599.

    Article  CAS  PubMed  Google Scholar 

  32. Sakanaka, C., Weiss, J. B., & Williams, L. T. (1998). Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proceedings of the National Academy of Sciences of the United States of America, 95(6), 3020–3023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aberle, H., et al. (1997). Beta-catenin is a target for the ubiquitin-proteasome pathway. The EMBO Journal, 16(13), 3797–3804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Munemitsu, S., et al. (1995). Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proceedings of the National Academy of Sciences of the United States of America, 92(7), 3046–3050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yost, C., et al. (1996). The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes & Development, 10(12), 1443–1454.

    Article  CAS  Google Scholar 

  36. Ikeda, S., et al. (1998). Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. The EMBO Journal, 17(5), 1371–1384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yamamoto, H., et al. (1998). Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Molecular and Cellular Biology, 18(5), 2867–2875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Seeling, J. M., et al. (1999). Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. Science, 283(5410), 2089–2091.

    Article  CAS  PubMed  Google Scholar 

  39. Gao, Z. H., et al. (2002). Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proceedings of the National Academy of Sciences of the United States of America, 99(3), 1182–1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Su, L. K., Vogelstein, B., & Kinzler, K. W. (1993). Association of the APC tumor suppressor protein with catenins. Science, 262(5140), 1734–1737.

    Article  CAS  PubMed  Google Scholar 

  41. Rubinfeld, B., et al. (1997). Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Research, 57(20), 4624–4630.

    CAS  PubMed  Google Scholar 

  42. Rubinfeld, B., et al. (1996). Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science, 272(5264), 1023–1026.

    Article  CAS  PubMed  Google Scholar 

  43. Liu, C., et al. (2002). Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 108(6), 837–847.

    Article  CAS  PubMed  Google Scholar 

  44. Behrens, J., et al. (1996). Functional interaction of beta-catenin with the transcription factor LEF-1. Nature, 382(6592), 638–642.

    Article  CAS  PubMed  Google Scholar 

  45. He, T. C., et al. (1998). Identification of c-MYC as a target of the APC pathway. Science, 281(5382), 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  46. Shtutman, M., et al. (1999). The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proceedings of the National Academy of Sciences of the United States of America, 96(10), 5522–5527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tetsu, O., & McCormick, F. (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature, 398(6726), 422–426.

    Article  CAS  PubMed  Google Scholar 

  48. Yamamoto, Y., et al. (2003). Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology, 37(3), 528–533.

    Article  CAS  PubMed  Google Scholar 

  49. Van der Flier, L. G., et al. (2007). The intestinal Wnt/TCF signature. Gastroenterology, 132(2), 628–632.

    Article  PubMed  CAS  Google Scholar 

  50. Fevr, T., et al. (2007). Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Molecular and Cellular Biology, 27(21), 7551–7559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Morin, P. J., Vogelstein, B., & Kinzler, K. W. (1996). Apoptosis and APC in colorectal tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 93(15), 7950–7954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chandra, S. H., et al. (2012). A common role for various human truncated adenomatous polyposis coli isoforms in the control of beta-catenin activity and cell proliferation. PLoS One, 7(4), e34479.

    Article  CAS  PubMed  Google Scholar 

  53. Sansom, O. J., et al. (2004). Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes & Development, 18(12), 1385–1390.

    Article  CAS  Google Scholar 

  54. Dow, L. E., et al. (2015). Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell, 161(7), 1539–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Strater, J., et al. (1995). In situ detection of enterocytic apoptosis in normal colonic mucosa and in familial adenomatous polyposis. Gut, 37(6), 819–825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. van de Wetering, M., et al. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell, 111(2), 241–250.

    Article  PubMed  Google Scholar 

  57. Senda, T., et al. (2007). Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Medical Molecular Morphology, 40(2), 68–81.

    Article  PubMed  Google Scholar 

  58. Korinek, V., et al. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science, 275(5307), 1784–1787.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang, F., White, R. L., & Neufeld, K. L. (2000). Phosphorylation near nuclear localization signal regulates nuclear import of adenomatous polyposis coli protein. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12577–12582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Galea, M. A., Eleftheriou, A., & Henderson, B. R. (2001). ARM domain-dependent nuclear import of adenomatous polyposis coli protein is stimulated by the B56 alpha subunit of protein phosphatase 2A. The Journal of Biological Chemistry, 276(49), 45833–45839.

    Article  CAS  PubMed  Google Scholar 

  61. Henderson, B. R. (2000). Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nature Cell Biology, 2(9), 653–660.

    Article  CAS  PubMed  Google Scholar 

  62. Neufeld, K. L., et al. (2000). APC-mediated downregulation of beta-catenin activity involves nuclear sequestration and nuclear export. EMBO Reports, 1(6), 519–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rosin-Arbesfeld, R., Townsley, F., & Bienz, M. (2000). The APC tumour suppressor has a nuclear export function. Nature, 406(6799), 1009–1012.

    Article  CAS  PubMed  Google Scholar 

  64. Rosin-Arbesfeld, R., et al. (2003). Nuclear export of the APC tumour suppressor controls beta-catenin function in transcription. The EMBO Journal, 22(5), 1101–1113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang, F., White, R. L., & Neufeld, K. L. (2001). Cell density and phosphorylation control the subcellular localization of adenomatous polyposis coli protein. Molecular and Cellular Biology, 21(23), 8143–8156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fagman, H., et al. (2003). Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation. Oncogene, 22(38), 6013–6022.

    Article  CAS  PubMed  Google Scholar 

  67. Davies, J. R., et al. (2004). Potential link between the NIMA mitotic kinase and nuclear membrane fission during mitotic exit in Aspergillus nidulans. Eukaryotic Cell, 3(6), 1433–1444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sierra, J., et al. (2006). The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes & Development, 20(5), 586–600.

    Article  CAS  Google Scholar 

  69. Choi, S. H., et al. (2013). α-Catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of Wnt target genes. Genes & Development, 27(22), 2473–2488.

    Article  CAS  Google Scholar 

  70. Hamada, F., & Bienz, M. (2004). The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. Developmental Cell, 7(5), 677–685.

    Article  CAS  PubMed  Google Scholar 

  71. Anderson, C. B., Neufeld, K. L., & White, R. L. (2002). Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proceedings of the National Academy of Sciences of the United States of America, 99(13), 8683–8688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kouzmenko, A. P., et al. (2008). Truncation mutations abolish chromatin-associated activities of adenomatous polyposis coli. Oncogene, 27(36), 4888–4899.

    Article  CAS  PubMed  Google Scholar 

  73. Zeineldin, M., et al. (2012). A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression. Oncogene, 31(19), 2423–2437.

    Article  CAS  PubMed  Google Scholar 

  74. Goel, A., et al. (2007). The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology, 132(1), 127–138.

    Article  CAS  PubMed  Google Scholar 

  75. Fodde, R., et al. (2001). Mutations in the APC tumour suppressor gene cause chromosomal instability. Nature Cell Biology, 3(4), 433–438.

    Article  CAS  PubMed  Google Scholar 

  76. Kaplan, K. B., et al. (2001). A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nature Cell Biology, 3(4), 429–432.

    Article  CAS  PubMed  Google Scholar 

  77. Dikovskaya, D., et al. (2007). Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. The Journal of Cell Biology, 176(2), 183–195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Green, R. A., Wollman, R., & Kaplan, K. B. (2005). APC and EB1 function together in mitosis to regulate spindle dynamics and chromosome alignment. Molecular Biology of the Cell, 16(10), 4609–4622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Trzepacz, C., et al. (1997). Phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) by the cyclin-dependent kinase p34. The Journal of Biological Chemistry, 272(35), 21681–21684.

    Article  CAS  PubMed  Google Scholar 

  80. Green, R. A., & Kaplan, K. B. (2003). Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. The Journal of Cell Biology, 163(5), 949–961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Groden, J., et al. (1995). Response of colon cancer cell lines to the introduction of APC, a colon-specific tumor suppressor gene. Cancer Research, 55(7), 1531–1539.

    CAS  PubMed  Google Scholar 

  82. Baeg, G. H., et al. (1995). The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. The EMBO Journal, 14(22), 5618–5625.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Heinen, C. D., et al. (2002). The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway. Gastroenterology, 123(3), 751–763.

    Article  CAS  PubMed  Google Scholar 

  84. Ishidate, T., et al. (2000). The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene, 19(3), 365–372.

    Article  CAS  PubMed  Google Scholar 

  85. Qian, J., et al. (2008). The APC tumor suppressor inhibits DNA replication by directly binding to DNA via its carboxyl terminus. Gastroenterology, 135(1), 152–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brocardo, M. G., Borowiec, J. A., & Henderson, B. R. (2011). Adenomatous polyposis coli protein regulates the cellular response to DNA replication stress. The International Journal of Biochemistry & Cell Biology, 43(9), 1354–1364.

    Article  CAS  Google Scholar 

  87. Zhang, Y., et al. (2009). Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nature Chemical Biology, 5(4), 217–219.

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, T., et al. (2001). Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Research, 61(24), 8664–8667.

    CAS  PubMed  Google Scholar 

  89. Steigerwald, K., et al. (2005). The APC tumor suppressor promotes transcription-independent apoptosis in vitro. Molecular Cancer Research, 3(2), 78–89.

    Article  CAS  PubMed  Google Scholar 

  90. Qian, J., et al. (2007). Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis. Oncogene, 26(33), 4872–4876.

    Article  CAS  PubMed  Google Scholar 

  91. Qian, J., et al. (2010). The mitochondrial protein hTID-1 partners with the caspase-cleaved adenomatous polyposis cell tumor suppressor to facilitate apoptosis. Gastroenterology, 138(4), 1418–1428.

    Article  CAS  PubMed  Google Scholar 

  92. Brocardo, M., et al. (2008). Mitochondrial targeting of adenomatous polyposis coli protein is stimulated by truncating cancer mutations: regulation of Bcl-2 and implications for cell survival. The Journal of Biological Chemistry, 283(9), 5950–5959.

    Article  CAS  PubMed  Google Scholar 

  93. Andreu, P., et al. (2005). Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development, 132(6), 1443–1451.

    Article  CAS  PubMed  Google Scholar 

  94. Korinek, V., et al. (1998). Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genetics, 19(4), 379–383.

    Article  CAS  PubMed  Google Scholar 

  95. Barker, N., et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165), 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  96. Nadauld, L. D., et al. (2004). Adenomatous polyposis coli control of retinoic acid biosynthesis is critical for zebrafish intestinal development and differentiation. The Journal of Biological Chemistry, 279(49), 51581–51589.

    Article  CAS  PubMed  Google Scholar 

  97. Nadauld, L. D., et al. (2006). Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases. The Journal of Biological Chemistry, 281(49), 37828–37835.

    Article  CAS  PubMed  Google Scholar 

  98. Nadauld, L. D., et al. (2005). The zebrafish retinol dehydrogenase, rdh1l, is essential for intestinal development and is regulated by the tumor suppressor adenomatous polyposis coli. The Journal of Biological Chemistry, 280(34), 30490–30495.

    Article  CAS  PubMed  Google Scholar 

  99. Jette, C., et al. (2004). The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L. The Journal of Biological Chemistry, 279(33), 34397–34405.

    Article  CAS  PubMed  Google Scholar 

  100. Sandoval, I. T., et al. (2017). A metabolic switch controls intestinal differentiation downstream of adenomatous polyposis coli (APC). eLife, 6, e22706.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Cheng, H., & Leblond, C. P. (1974). Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. The American Journal of Anatomy, 141(4), 537–561.

    Article  CAS  PubMed  Google Scholar 

  102. Rosin-Arbesfeld, R., Ihrke, G., & Bienz, M. (2001). Actin-dependent membrane association of the APC tumour suppressor in polarized mammalian epithelial cells. The EMBO Journal, 20(21), 5929–5939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kawasaki, Y., et al. (2000). Asef, a link between the tumor suppressor APC and G-protein signaling. Science, 289(5482), 1194–1197.

    Article  CAS  PubMed  Google Scholar 

  104. Watanabe, T., et al. (2004). Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Developmental Cell, 7(6), 871–883.

    Article  CAS  PubMed  Google Scholar 

  105. Sudhaharan, T., et al. (2011). Rho GTPase Cdc42 is a direct interacting partner of adenomatous polyposis coli protein and can alter its cellular localization. PLoS One, 6(2), e16603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Moseley, J. B., et al. (2007). Regulated binding of adenomatous polyposis coli protein to actin. The Journal of Biological Chemistry, 282(17), 12661–12668.

    Article  CAS  PubMed  Google Scholar 

  107. Okada, K., et al. (2010). Adenomatous polyposis coli protein nucleates actin assembly and synergizes with the formin mDia1. The Journal of Cell Biology, 189(7), 1087–1096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Juanes, M. A., et al. (2017). Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover. The Journal of Cell Biology, 216(9), 2859–2875.

    PubMed  Google Scholar 

  109. Aberle, H., Schwartz, H., & Kemler, R. (1996). Cadherin-catenin complex: Protein interactions and their implications for cadherin function. Journal of Cellular Biochemistry, 61(4), 514–523.

    Article  CAS  PubMed  Google Scholar 

  110. Faux, M. C., et al. (2004). Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion. Journal of Cell Science, 117(Pt 3), 427–439.

    CAS  PubMed  Google Scholar 

  111. Hulsken, J., Birchmeier, W., & Behrens, J. (1994). E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. The Journal of Cell Biology, 127(6 Pt 2), 2061–2069.

    Article  CAS  PubMed  Google Scholar 

  112. Nelson, S. A., et al. (2012). Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems. Disease Models & Mechanisms, 5(6), 940–947.

    Article  CAS  Google Scholar 

  113. Matsumine, A., et al. (1996). Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science, 272(5264), 1020–1023.

    Article  CAS  PubMed  Google Scholar 

  114. Takizawa, S., et al. (2006). Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli. Genes to Cells, 11(4), 453–464.

    Article  CAS  PubMed  Google Scholar 

  115. Nathke, I. S., et al. (1996). The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. The Journal of Cell Biology, 134(1), 165–179.

    Article  CAS  PubMed  Google Scholar 

  116. Munemitsu, S., et al. (1994). The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Research, 54(14), 3676–3681.

    CAS  PubMed  Google Scholar 

  117. Zumbrunn, J., et al. (2001). Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Current Biology, 11(1), 44–49.

    Article  CAS  PubMed  Google Scholar 

  118. Mogensen, M. M., et al. (2002). The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarized epithelial cells. The Journal of Cell Biology, 157(6), 1041–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Su, L. K., et al. (1995). APC binds to the novel protein EB1. Cancer Research, 55(14), 2972–2977.

    CAS  PubMed  Google Scholar 

  120. Iizuka-Kogo, A., Shimomura, A., & Senda, T. (2005). Colocalization of APC and DLG at the tips of cellular protrusions in cultured epithelial cells and its dependency on cytoskeletons. Histochemistry and Cell Biology, 123(1), 67–73.

    Article  CAS  PubMed  Google Scholar 

  121. Kroboth, K., et al. (2007). Lack of adenomatous polyposis coli protein correlates with a decrease in cell migration and overall changes in microtubule stability. Molecular Biology of the Cell, 18(3), 910–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mili, S., Moissoglu, K., & Macara, I. G. (2008). Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. Nature, 453(7191), 115–119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Marshall, T. W., et al. (2011). The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium. Molecular Biology of the Cell, 22(21), 3962–3970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bellis, J., et al. (2012). The tumor suppressor Apc controls planar cell polarities central to gut homeostasis. The Journal of Cell Biology, 198(3), 331–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mahmoud, N. N., et al. (1997). Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration. Cancer Research, 57(22), 5045–5050.

    CAS  PubMed  Google Scholar 

  126. Wong, M. H., et al. (1996). Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proceedings of the National Academy of Sciences of the United States of America, 93(18), 9588–9593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim, K. P., et al. (2017). Paired primary and metastatic tumor analysis of somatic mutations in synchronous and metachronous colorectal cancer. Cancer Research and Treatment, 49(1), 161–167.

    Article  PubMed  Google Scholar 

  128. Leung, M. L., et al. (2017). Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer. Genome Research, 27(8), 1287–1299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Brabletz, T., et al. (2001). Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences of the United States of America, 98(18), 10356–10361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bracke, M. E., Van Roy, F. M., & Mareel, M. M. (1996). The E-cadherin/catenin complex in invasion and metastasis. Current Topics in Microbiology and Immunology, 213(Pt 1), 123–161.

    CAS  PubMed  Google Scholar 

  131. Jamora, C., et al. (2003). Links between signal transduction, transcription and adhesion in epithelial bud development. Nature, 422(6929), 317–322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Conacci-Sorrell, M., et al. (2003). Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. The Journal of Cell Biology, 163(4), 847–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gradl, D., Kuhl, M., & Wedlich, D. (1999). The Wnt/Wg signal transducer beta-catenin controls fibronectin expression. Molecular and Cellular Biology, 19(8), 5576–5587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hlubek, F., et al. (2001). Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. Cancer Research, 61(22), 8089–8093.

    CAS  PubMed  Google Scholar 

  135. Crawford, H. C., et al. (1999). The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene, 18(18), 2883–2891.

    Article  CAS  PubMed  Google Scholar 

  136. Brabletz, T., et al. (1999). Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. The American Journal of Pathology, 155(4), 1033–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Takahashi, M., et al. (2002). Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers. Oncogene, 21(38), 5861–5867.

    Article  CAS  PubMed  Google Scholar 

  138. Gavert, N., et al. (2007). Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer Research, 67(16), 7703–7712.

    Article  CAS  PubMed  Google Scholar 

  139. Mann, B., et al. (1999). Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proceedings of the National Academy of Sciences of the United States of America, 96(4), 1603–1608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wielenga, V. J., et al. (1999). Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. The American Journal of Pathology, 154(2), 515–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Conacci-Sorrell, M. E., et al. (2002). Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes & Development, 16(16), 2058–2072.

    Article  CAS  Google Scholar 

  142. Gavert, N., et al. (2005). L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. The Journal of Cell Biology, 168(4), 633–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Batlle, E., et al. (2002). β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell, 111(2), 251–263.

    Article  CAS  PubMed  Google Scholar 

  144. Vignjevic, D., et al. (2007). Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Research, 67(14), 6844–6853.

    Article  CAS  PubMed  Google Scholar 

  145. Hlubek, F., et al. (2007). Heterogeneous expression of Wnt/beta-catenin target genes within colorectal cancer. International Journal of Cancer, 121(9), 1941–1948.

    Article  CAS  PubMed  Google Scholar 

  146. Todaro, M., et al. (2014). CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell, 14(3), 342–356.

    Article  CAS  PubMed  Google Scholar 

  147. Zilberberg, A., Lahav, L., & Rosin-Arbesfeld, R. (2010). Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut, 59(4), 496–507.

    Article  CAS  PubMed  Google Scholar 

  148. Virmani, A. K., et al. (2001). Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas. Clinical Cancer Research, 7(7), 1998–2004.

    CAS  PubMed  Google Scholar 

  149. Macnab, S. A., et al. (2011). Herpesvirus saimiri-mediated delivery of the adenomatous polyposis coli tumour suppressor gene reduces proliferation of colorectal cancer cells. International Journal of Oncology, 39(5), 1173–1181.

    CAS  PubMed  Google Scholar 

  150. Sansom, O. J., et al. (2007). Myc deletion rescues Apc deficiency in the small intestine. Nature, 446(7136), 676–679.

    Article  CAS  PubMed  Google Scholar 

  151. Reed, K. R., et al. (2008). B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver. Proceedings of the National Academy of Sciences of the United States of America, 105(48), 18919–18923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wilkins, J. A., & Sansom, O. J. (2008). C-Myc is a critical mediator of the phenotypes of Apc loss in the intestine. Cancer Research, 68(13), 4963–4966.

    Article  CAS  PubMed  Google Scholar 

  153. Schepers, A. G., et al. (2012). Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science, 337(6095), 730–735.

    Article  CAS  PubMed  Google Scholar 

  154. Garber, K. (2009). Drugging the Wnt pathway: problems and progress. Journal of the National Cancer Institute, 101(8), 548–550.

    Article  PubMed  Google Scholar 

  155. Shitashige, M., et al. (2010). Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Research, 70(12), 5024–5033.

    Article  CAS  PubMed  Google Scholar 

  156. Lu, B., et al. (2016). Wnt drug discovery: weaving through the screens, patents and clinical trials. Cancers (Basel), 8(9), 82.

    Article  Google Scholar 

  157. Vincan, E., & Barker, N. (2008). The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clinical & Experimental Metastasis, 25(6), 657–663.

    Article  CAS  Google Scholar 

  158. Chen, B., et al. (2009). Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chemical Biology, 5(2), 100–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Voloshanenko, O., et al. (2013). Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nature Communications, 4, 2610.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Liu, J., et al. (2013). Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proceedings of the National Academy of Sciences of the United States of America, 110(50), 20224–20229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Madan, B., et al. (2016). Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene, 35(17), 2197–2207.

    Article  CAS  PubMed  Google Scholar 

  162. Gurney, A., et al. (2012). Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proceedings of the National Academy of Sciences of the United States of America, 109(29), 11717–11722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Fischer, M. M., et al. (2017). WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Science Advances, 3(6), e1700090.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Thorne, C. A., et al. (2010). Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nature Chemical Biology, 6(11), 829–836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Huang, S. M., et al. (2009). Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature, 461(7264), 614–620.

    Article  CAS  PubMed  Google Scholar 

  166. Waaler, J., et al. (2012). A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Research, 72(11), 2822–2832.

    Article  CAS  PubMed  Google Scholar 

  167. Lau, T., et al. (2013). A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Research, 73(10), 3132–3144.

    Article  CAS  PubMed  Google Scholar 

  168. Larriba, M. J., et al. (2011). Vitamin D receptor deficiency enhances Wnt/beta-catenin signaling and tumor burden in colon cancer. PLoS One, 6(8), e23524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Palmer, H. G., et al. (2001). Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. The Journal of Cell Biology, 154(2), 369–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Shah, S., et al. (2006). The molecular basis of vitamin D receptor and beta-catenin crossregulation. Molecular Cell, 21(6), 799–809.

    Article  PubMed  CAS  Google Scholar 

  171. Lepourcelet, M., et al. (2004). Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell, 5(1), 91–102.

    Article  CAS  PubMed  Google Scholar 

  172. Emami, K. H., et al. (2004). A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proceedings of the National Academy of Sciences of the United States of America, 101(34), 12682–12687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Mahmoudi, T., et al. (2009). The kinase TNIK is an essential activator of Wnt target genes. The EMBO Journal, 28(21), 3329–3340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Shitashige, M., et al. (2008). Regulation of Wnt signaling by the nuclear pore complex. Gastroenterology, 134(7), 1961–1971, 1971 e1–4.

  175. Masuda, M., et al. (2016). TNIK inhibition abrogates colorectal cancer stemness. Nature Communications, 7, 12586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Morton, J. P., Myant, K. B., & Sansom, O. J. (2011). A FAK-PI-3K-mTOR axis is required for Wnt-Myc driven intestinal regeneration and tumorigenesis. Cell Cycle, 10(2), 173–175.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Debbie Knight, Research Associate in the Department of Pathology at The Ohio State University Wexner Medical Center, for performance of key immunohistochemical staining experiments, image generation, and design and construction of figures.

Funding

The study received financial support from NIH Awards R01CA063507 (J.G.), UL1TR001070 (J.G.), F31CA174260 (W.H.), HHMI MED into GRAD (W.H.), and Pelotonia Fellowship Program (W.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutions or the National Institutes of Health.

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  1. Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 460 W. 12th Ave. 986 BRT, Columbus, OH, 43210, USA

    William Hankey & Joanna Groden

  2. Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA

    Wendy L. Frankel

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  1. William Hankey
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Correspondence to Joanna Groden.

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Hankey, W., Frankel, W.L. & Groden, J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting. Cancer Metastasis Rev 37, 159–172 (2018). https://doi.org/10.1007/s10555-017-9725-6

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