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Review
. 2018 Aug;23(8):900-911.
doi: 10.1634/theoncologist.2017-0677. Epub 2018 Apr 5.

The Role of Notch3 in Cancer

Zviadi Aburjania  1 , Samuel Jang  1 , Jason Whitt  1 , Renata Jaskula-Stzul  1 , Herbert Chen  1 , J Bart Rose  2
Affiliations
Review

The Role of Notch3 in Cancer

Zviadi Aburjania et al. Oncologist. 2018 Aug.

Abstract

The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue-specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling.

Implications for practice: The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity.

Keywords: CADASIL; Cancer; Notch3; Tumor.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
The Notch pathway, showing therapeutic points for targeting Notch3. (1) HDAC inhibitors can enhance Notch3 gene transcription. (2) Notch3 mRNA translation can be inhibited by miRNA. (3) Furin‐like convertase inhibitors can inhibit Notch3 protein folding in the Golgi apparatus. (4) Blocking antibodies can be used to block Notch3 extracellular domain and prevent its interaction with the ligand. (5) ADAM and gamma‐secretase inhibitors can be used to prevent Notch3 protein cleavage and release of Notch3 intracellular domain. (6) Notch3 is translocated to the nucleus, it binds to transcription factors and modifies target gene transcription. Abbreviations: ADAM, disintegrin and metalloprotease; CSL, CBF1/Suppressor of Hairless/Lag‐1; HDACi, histone deacetylase inhibitor; MAML, mastermind‐like protein 1; miRNA, microRNA; NICD3, Notch3 intracellular domain.
See this image and copyright information in PMC

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