Notch Signalling in Cancer


The Notch pathway is an evolutionarily conserved signalling pathway involved in the development of diverse organisms from drosophila to humans. It plays a pivotal role in maintenance of stem cells and cell‐fate determination in both developing embryos and adult organisms. Aberrant Notch signalling is oncogenic and is documented in various cancers such as cervical, breast, skin, colon, pancreatic, leukaemia, brain tumour and so on. Genome defects including both genetic and epigenetic alterations contribute to cancer development. Both Notch gain‐of‐function and loss‐of‐function mutations have been reported in various cancers. On the basis of the type of tissue, Notch genes are found to function as both oncogenes and tumour‐suppressor genes. Epigenetic alterations of Notch genes including DNA (deoxyribonucleic acid) methylation and histone modifications contribute to cancer development through transcription regulation, resulting in inappropriate activation or silencing of genes. Thus, Notch pathway plays an important role in tumour development through genetic and epigenetic modifications in several different ways.

Key Concepts

  • Notch pathway is an evolutionarily conserved cell‐signalling pathway involved in the development of both vertebrate and invertebrate species.
  • It is responsible for communication between adjacent cells controlling multiple cell differentiation through regulation of gene expression during embryonic and adult life.
  • Aberrant Notch signalling is linked with various human diseases including cancers by modifying the developmental state of the cells and subsequently maintaining the cells in an undifferentiated or proliferative fate.
  • Abnormal Notch signalling is found to influence oncogenesis through genome defects involving both genetic and epigenetic alterations.
  • Depending on the cellular context, altered Notch pathway genes can act either as oncogenes or tumour‐suppressor genes.
  • The first reported Notch mutation was the chromosome translocation in T‐cell acute lymphoblastic leukaemia patients creating an active and oncogenic Notch1. Since then, Notch mutations, both gain‐of‐function and loss‐of‐function, have been identified in various cancers.
  • Promoter hypermethylation in Notch genes is more common in cancer compared to hypomethylation.
  • Histone modifications are covalent, and among various forms, lysine acetylation and lysine/arginine methylation are most common in cancer.

Keywords: Notch‐signalling pathway; mutation; gene expression; epigenetics; cancer

Figure 1. Schematic representation of Notch‐signalling pathway.


Agrawal N, Frederick MJ, Pickering CR, et al. (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333 (6046): 1154–1157.

Banerjee D, Hernandez SL, Garcia A, et al. (2015) Notch suppresses angiogenesis and progression of hepatic metastases. Cancer Research 75 (8): 1592–1602.

Brou C, Logeat F, Gupta N, et al. (2000) A novel proteolytic cleavage involved in notch signalling: the role of the disintegrin‐metalloprotease TACE. Molecular Cell 5 (2): 207–216.

Chen J, Imanaka N, Chen J, et al. (2010) Hypoxia potentiates Notch signalling in breast cancer leading to decreased E cadherin expression and increased cell migration and invasion. British Journal of Cancer 102 (2): 351–360.

Chen Z, Yang Y, Liu B, et al. (2015) Promotion of metastasis‐associated gene expression in survived PANC‐1 cells following trichostatin A treatment. Anti‐Cancer Agents in Medicinal Chemistry 15 (10): 1317–1325.

Dang TP, Gazdar AF, Virmani AK, et al. (2000) Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. Journal of the National Cancer Institute 92 (16): 1355–1357.

D'Angelo RC, Ouzounova M, Davis A, et al. (2015) Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Molecular Cancer Therapeutics 14 (3): 779–787.

Ding XY, Ding J, Wu K, et al. (2012) Cross‐talk between endothelial cells and tumor via delta‐like ligand 4/Notch/PTEN signalling inhibits lung cancer growth. Oncogene 31 (23): 2899–2906.

Dumont AG, Yang Y, Reynoso D, et al. (2012) Anti‐tumor effects of the Notch pathway in gastrointestinal stromal tumors. Carcinogenesis 33 (9): 1674–1683.

Ellisen LW, Bird J, West DC, et al. (1991) TAN‐1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66 (4): 649–661.

Fabbri G, Rasi S, Rossi D, et al. (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. The Journal of Experimental Medicine 208 (7): 1389–1401.

Fan X, Khaki L, Zhu TS, et al. (2010) NOTCH pathway blockade depletes CD133‐positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28 (1): 5–16.

Hanlon L, Avila JL, Demarest RM, et al. (2010) Notch1 functions as a tumor suppressor in a model of K‐ras‐induced pancreatic ductal adenocarcinoma. Cancer Research 70 (11): 4280–4286.

Hassan KA, Wang L, Korkaya H, et al. (2013) Notch pathway activity identifies cells with cancer stem cell‐like properties and correlates with worse survival in lung adenocarcinoma. Clinical Cancer Research 19 (8): 1972–1980.

Ilagan MX and Kopan R (2007) SnapShot: Notch signalling pathway. Cell 128 (6): 1246.

Izumchenko E, Sun K, Jones S, et al. (2015) Notch1 mutations are drivers of oral tumorigenesis. Cancer Prevention Research 8 (4): 277–286.

Jiao X, Wood LD, Lindman M, et al. (2012) Somatic mutations in the Notch, NF‐KB, PIK3CA, and Hedgehog pathways in human breast cancers. Genes, Chromosomes & Cancer 51 (5): 480–489.

Jithesh PV, Risk JM, Schache AG, et al. (2013) The epigenetic landscape of oral squamous cell carcinoma. British Journal of Cancer 108 (2): 370–379.

Kannan S, Sutphin RM, Hall MG, et al. (2013) Notch activation inhibits AML growth and survival: a potential therapeutic approach. The Journal of Experimental Medicine 210 (2): 321–337.

Klinakis A, Lobry C, Abdel‐Wahab O, et al. (2011) A novel tumour‐suppressor function for the Notch pathway in myeloid leukaemia. Nature 473 (7346): 230–233.

Kuang SQ, Fang Z, Zweidler‐McKay PA, et al. (2013) Epigenetic inactivation of Notch‐Hes pathway in human B‐cell acute lymphoblastic leukemia. PLoS One 8 (4): e61807.

Lee SH, Jeong EG, Yoo NJ, et al. (2007) Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias. Acta Pathologica, Microbiologica et Immunologica Scandinavica 115 (12): 1357–1363.

Liu Q, Zheng JM, Chen JK, et al. (2014) Histone deacetylase 5 promotes the proliferation of glioma cells by upregulation of Notch 1. Molecular Medicine Reports 10 (4): 2045–2050.

Maraver A, Fernandez‐Marcos PJ, Cash TP, et al. (2015) NOTCH pathway inactivation promotes bladder cancer progression. The Journal of Clinical Investigation 125 (2): 824–830.

Massie CE, Spiteri I, Ross‐Adams H, et al. (2015) HES5 silencing is an early and recurrent change in prostate tumourigenesis. Endocrine‐Related Cancer 22 (2): 131–144.

Palermo R, Checquolo S, Giovenco A, et al. (2012) Acetylation controls Notch3 stability and function in T‐cell leukemia. Oncogene 31 (33): 3807–3817.

Piazzi G, Fini L, Selgrad M, et al. (2011) Epigenetic regulation of Delta‐Like1 controls Notch1 activation in gastric cancer. Oncotarget 2 (12): 1291–1301.

Piazzi G, Bazzoli F and Ricciardiello L (2012) Epigenetic silencing of Notch signalling in gastrointestinal cancers. Cell Cycle 11 (23): 4323–4327.

Razumilava N and Gores GJ (2013) Notch‐driven carcinogenesis: the merging of hepatocellular cancer and cholangiocarcinoma into a common molecular liver cancer subtype. Journal of Hepatology 58 (6): 1244–1245.

Sivasankaran B, Degen M, Ghaffari A, et al. (2009) Tenascin‐C is a novel RBPJk‐induced target gene for Notch signalling in gliomas. Cancer Research 69 (2): 458–465.

Stransky N, Egloff AM, Tward AD, et al. (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333 (6046): 1157–1160.

Sun W, Gaykalova DA, Ochs MF, et al. (2014) Activation of the NOTCH pathway in head and neck cancer. Cancer Research 74 (4): 1091–1104.

Tian C, Yu Y, Jia Y, et al. (2015) HES1 activation suppresses proliferation of leukemia cells in acute myeloid leukemia. Annals of Hematology 94 (9): 1477–1483.

Viatour P, Ehmer U, Saddic LA, et al. (2011) Notch signalling inhibits hepatocellular carcinoma following inactivation of the RB pathway. The Journal of Experimental Medicine 208 (10): 1963–1976.

Villanueva A, Alsinet C, Yanger K, et al. (2012) Notch signalling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143 (6): 1660–1669.e7.

Wang NJ, Sanborn Z, Arnett KL, et al. (2011) Loss‐of‐function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America 108 (43): 17761–17766.

Wang H, Huang X, Zhang J, et al. (2014) The expression of VEGF and Dll4/Notch pathway molecules in ovarian cancer. Clinica Chimica Acta 436: 243–248.

Wang K, Zhang Q, Li D, et al. (2015) PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple‐negative breast cancer sensitive to a γ‐secretase inhibitor. Clinical Cancer Research 21 (6): 1487–1496.

Weng AP, Ferrando AA, Lee W, et al. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306 (5694): 269–271.

Westhoff B, Colaluca IN, D'Ario G, et al. (2009) Alterations of the Notch pathway in lung cancer. Proceedings of the National Academy of Sciences of the United States of America 106 (52): 22293–22298.

Yabuuchi S, Pai SG, Campbell NR, et al. (2013) Notch signalling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Letters 335 (1): 41–51.

Yamamoto S, Tateishi K, Kudo Y, et al. (2013) Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. Carcinogenesis 34 (10): 2380–2388.

Ye YZ, Zhang ZH, Fan XY, et al. (2013) Notch3 overexpression associates with poor prognosis in human non‐small‐cell lung cancer. Medical Oncology 30 (2): 595.

Zage PE, Nolo R, Fang W, et al. (2012) Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatric Blood & Cancer 58 (5): 682–689.

Zampieri M, Ciccarone F, Palermo R, et al. (2014) The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells. Biochimica et Biophysica Acta 1839 (9): 813–825.

Zhang J, Yin XJ, Xu CJ, et al. (2015) The histone deacetylase SIRT6 inhibits ovarian cancer cell proliferation via down‐regulation of Notch 3 expression. European Review for Medical and Pharmacological Sciences 19 (5): 818–824.

Further Reading

Allenspach EJ, Maillard I, Aster JC, et al. (2002) Notch signalling in cancer. Cancer Biology & Therapy 1 (5): 466–476.

Bolós V, Grego‐Bessa J and de la Pompa JL (2007) Notch signalling in development and cancer. Endocrine Reviews 28 (3): 339–363.

Egloff AM and Grandis JR (2012) Molecular pathways: context‐dependent approaches to Notch targeting as cancer therapy. Clinical Cancer Research 18 (19): 5188–5195.

Leong KG and Karsan A (2006) Recent insights into the role of Notch signalling in tumorigenesis. Blood 107 (6): 2223–2233.

Lobry C, Oh P and Aifantis I (2011) Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. The Journal of Experimental Medicine 208 (10): 1931–1935.

Mao L (2015) NOTCH mutations: multiple faces in human malignancies. Cancer Prevention Research 8 (4): 259–261.

Nickoloff BJ, Osborne BA and Miele L (2003) Notch signalling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene 22 (42): 6598–6608.

Ntziachristos P, Lim JS, Sage J, et al. (2014) From fly wings to targeted cancer therapies: a centennial for notch signalling. Cancer Cell 25 (3): 318–334.

Ranganathan P, Weaver KL and Capobianco AJ (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nature reviews. Cancer 11 (5): 338–351.

Wang Z, Li Y, Banerjee S, et al. (2008) Exploitation of the Notch signalling pathway as a novel target for cancer therapy. Anticancer Research 28 (6A): 3621–3630.

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Aithal, Madhuri GS, and Narayanappa, Rajeswari(Dec 2015) Notch Signalling in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024868]