Notch1-dependent regulation of p27 determines cell fate in colorectal cancer

Hristova,Nevyana  R.; Tagscherer,Katrin   E.; Fassl,Anne; Kopitz,Juergen; Roth,Wilfried

doi:10.3892/ijo.2013.2140

Notch1-dependent regulation of p27 determines cell fate in colorectal cancer

Authors:
- Nevyana R. Hristova
- Katrin E. Tagscherer
- Anne Fassl
- Juergen Kopitz
- Wilfried Roth
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Affiliations: Molecular Tumor Pathology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany, Institute of Pathology, University of Heidelberg, D-69120 Heidelberg, Germany
Published online on: October 17, 2013 https://doi.org/10.3892/ijo.2013.2140
Pages: 1967-1975

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Abstract

Enhanced Notch signaling contributes to uncontrolled cell growth and cell death resistance in cancer. Here, we demonstrate that in colorectal carcinoma cells the Notch1-dependent activation of cell cycle and proliferation is mediated by repression of the cyclin-dependent kinase inhibitor (CDKI) p27. The half-life of p27 significantly increased after siRNA‑mediated knockdown of Notch1. Notch1 depletion altered the transcription of SKP2, KPC1 and KPC2, which are E3-ubiquitin ligase subunits targeting p27 for proteasomal degradation in the nucleus and the cytoplasm, respectively. As a consequence, the levels of p27 in both cellular fractions were elevated upon Notch1 knockdown. Importantly, the downregulation of Notch1 significantly sensitized colorectal cancer cells to chemotherapy and ionizing radiation. Our findings support an important role of p27 in Notch1-dependent oncogenic signaling and suggest that Notch1 is a promising target for an experimental therapy of colorectal carcinoma.

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1.	Bray SJ: Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 7:678–689. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Radtke F and Raj K: The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 3:756–767. 2003. View Article : Google Scholar : PubMed/NCBI
3.	Benedito R, Roca C, Sorensen I, et al: The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 137:1124–1135. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Fre S, Huyghe M, Mourikis P, Robine S, Louvard D and Artavanis-Tsakonas S: Notch signals control the fate of immature progenitor cells in the intestine. Nature. 435:964–968. 2005. View Article : Google Scholar : PubMed/NCBI
5.	Schroder N and Gossler A: Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns. 2:247–250. 2002. View Article : Google Scholar : PubMed/NCBI
6.	Jensen J, Pedersen EE, Galante P, et al: Control of endodermal endocrine development by Hes-1. Nat Genet. 24:36–44. 2000. View Article : Google Scholar : PubMed/NCBI
7.	Riccio O, van Gijn ME, Bezdek AC, et al: Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 9:377–383. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Qiao L and Wong BC: Role of Notch signaling in colorectal cancer. Carcinogenesis. 30:1979–1986. 2009. View Article : Google Scholar : PubMed/NCBI
9.	Zhang Y, Li B, Ji ZZ and Zheng PS: Notch1 regulates the growth of human colon cancers. Cancer. 116:5207–5218. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Zolkiewska A: ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci. 65:2056–2068. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Fortini ME: Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol. 3:673–684. 2002. View Article : Google Scholar : PubMed/NCBI
12.	Katoh M and Katoh M: Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Int J Oncol. 31:461–466. 2007.PubMed/NCBI
13.	Chu IM, Hengst L and Slingerland JM: The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anti-cancer therapy. Nat Rev Cancer. 8:253–267. 2008. View Article : Google Scholar : PubMed/NCBI
14.	Lu Z and Hunter T: Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle. 9:2342–2352. 2010. View Article : Google Scholar : PubMed/NCBI
15.	Kamura T, Hara T, Matsumoto M, et al: Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase. Nat Cell Biol. 6:1229–1235. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K and Nakayama KI: Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem. 277:14355–14358. 2002. View Article : Google Scholar
17.	Castro F, Dirks WG, Fahnrich S, Hotz-Wagenblatt A, Pawlita M and Schmitt M: High-throughput SNP-based authentication of human cell lines. Int J Cancer. 132:308–314. 2013. View Article : Google Scholar : PubMed/NCBI
18.	Schmitt M and Pawlita M: High-throughput detection and multiplex identification of cell contaminations. Nucleic Acids Res. 37:e1192009. View Article : Google Scholar : PubMed/NCBI
19.	Sikandar SS, Pate KT, Anderson S, et al: NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 70:1469–1478. 2010. View Article : Google Scholar
20.	Sarmento LM, Huang H, Limon A, et al: Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation. J Exp Med. 202:157–168. 2005. View Article : Google Scholar : PubMed/NCBI
21.	Sharma VM, Calvo JA, Draheim KM, et al: Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol. 26:8022–8031. 2006. View Article : Google Scholar : PubMed/NCBI
22.	Weng AP, Millholland JM, Yashiro-Ohtani Y, et al: c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20:2096–2109. 2006. View Article : Google Scholar : PubMed/NCBI
23.	Palomero T, Sulis ML, Cortina M, et al: Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 13:1203–1210. 2007. View Article : Google Scholar : PubMed/NCBI
24.	Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S and Efstratiadis A: Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA. 103:9262–9267. 2006. View Article : Google Scholar : PubMed/NCBI
25.	Ling H, Sylvestre JR and Jolicoeur P: Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene. 29:4543–4554. 2010. View Article : Google Scholar : PubMed/NCBI
26.	Cohen B, Shimizu M, Izrailit J, et al: Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Res Treat. 123:113–124. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Stahl M, Ge C, Shi S, Pestell RG and Stanley P: Notch1-induced transformation of RKE-1 cells requires up-regulation of cyclin D1. Cancer Res. 66:7562–7570. 2006. View Article : Google Scholar : PubMed/NCBI
28.	Sicinska E, Aifantis I, Le Cam L, et al: Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell. 4:451–461. 2003. View Article : Google Scholar : PubMed/NCBI
29.	Ronchini C and Capobianco AJ: Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol. 21:5925–5934. 2001. View Article : Google Scholar : PubMed/NCBI
30.	Gotte M, Greve B, Kelsch R, et al: The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via Notch-1 and p21WAF1/CIP1. Int J Cancer. 129:2042–2049. 2011. View Article : Google Scholar : PubMed/NCBI
31.	Dohda T, Maljukova A, Liu L, et al: Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines. Exp Cell Res. 313:3141–3152. 2007. View Article : Google Scholar : PubMed/NCBI
32.	Hara T, Kamura T, Kotoshiba S, et al: Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle. Mol Cell Biol. 25:9292–9303. 2005. View Article : Google Scholar : PubMed/NCBI
33.	Lu Y, Adegoke OA, Nepveu A, et al: USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1. Mol Cell Biol. 29:547–558. 2009. View Article : Google Scholar : PubMed/NCBI
34.	Zhao J, Zhang S, Wu X, et al: KPC1 expression and essential role after acute spinal cord injury in adult rat. Neurochem Res. 36:549–558. 2011. View Article : Google Scholar : PubMed/NCBI
35.	Lu C, Huang X, Zhang X, et al: miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood. 117:4293–4303. 2011. View Article : Google Scholar : PubMed/NCBI
36.	Susaki E, Nakayama K and Nakayama KI: Cyclin D2 translocates p27 out of the nucleus and promotes its degradation at the G0-G1 transition. Mol Cell Biol. 27:4626–4640. 2007. View Article : Google Scholar : PubMed/NCBI
37.	Giovannini C, Gramantieri L, Minguzzi M, et al: CDKN1C/P57 is regulated by the Notch target gene Hes1 and induces senescence in human hepatocellular carcinoma. Am J Pathol. 181:413–422. 2012. View Article : Google Scholar : PubMed/NCBI
38.	See WL, Heinberg AR, Holland EC and Resh MD: p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo. Cell Cycle. 9:1562–1567. 2010. View Article : Google Scholar : PubMed/NCBI
39.	Wander SA, Zhao D and Slingerland JM: p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies. Clin Cancer Res. 17:12–18. 2011. View Article : Google Scholar : PubMed/NCBI
40.	Noguchi T, Kikuchi R, Ono K, Takeno S, Moriyama H and Uchida Y: Prognostic significance of p27/kip1 and apoptosis in patients with colorectal carcinoma. Oncol Rep. 10:827–831. 2003.PubMed/NCBI
41.	Manne U, Jhala NC, Jones J, et al: Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage. Clin Cancer Res. 10:1743–1752. 2004. View Article : Google Scholar : PubMed/NCBI
42.	Wu JT, Kakar S, Nelson RL, et al: Prognostic significance of DCC and p27Kip1 in colorectal cancer. Appl Immunohistochem Mol Morphol. 13:45–54. 2005. View Article : Google Scholar : PubMed/NCBI
43.	Rosati G, Chiacchio R, Reggiardo G, De Sanctis D and Manzione L: Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. Tumour Biol. 25:258–263. 2004. View Article : Google Scholar : PubMed/NCBI
44.	Watson NF, Durrant LG, Scholefield JH, et al: Cytoplasmic expression of p27(kip1) is associated with a favourable prognosis in colorectal cancer patients. World J Gastroenterol. 12:6299–6304. 2006.PubMed/NCBI
45.	Gysin S, Lee SH, Dean NM and McMahon M: Pharmacologic inhibition of RAF→MEK→ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 65:4870–4880. 2005.
46.	Hong F, Larrea MD, Doughty C, Kwiatkowski DJ, Squillace R and Slingerland JM: mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell. 30:701–711. 2008. View Article : Google Scholar : PubMed/NCBI
47.	Fassl A, Tagscherer KE, Richter J, et al: Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1. Oncogene. 31:4698–4708. 2012. View Article : Google Scholar : PubMed/NCBI
48.	Liu WH, Hsiao HW, Tsou WI and Lai MZ: Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation. EMBO J. 26:1660–1669. 2007. View Article : Google Scholar : PubMed/NCBI
49.	Beverly LJ, Felsher DW and Capobianco AJ: Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. Cancer Res. 65:7159–7168. 2005. View Article : Google Scholar : PubMed/NCBI
50.	Meng RD, Shelton CC, Li YM, et al: gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 69:573–582. 2009. View Article : Google Scholar
51.	Akiyoshi T, Nakamura M, Yanai K, et al: Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology. 134:131–144. 2008. View Article : Google Scholar : PubMed/NCBI
52.	Pannuti A, Foreman K, Rizzo P, et al: Targeting Notch to target cancer stem cells. Clin Cancer Res. 16:3141–3152. 2010. View Article : Google Scholar : PubMed/NCBI
53.	Real PJ, Tosello V, Palomero T, et al: Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 15:50–58. 2009. View Article : Google Scholar : PubMed/NCBI
54.	Van Es JH, van Gijn ME, Riccio O, et al: Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 435:959–963. 2005.PubMed/NCBI
55.	Wu Y, Cain-Hom C, Choy L, et al: Therapeutic antibody targeting of individual Notch receptors. Nature. 464:1052–1057. 2010. View Article : Google Scholar : PubMed/NCBI