N otch Signalling in Cancer

Abstract 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.