Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Abstract

The dysregulation of Notch signaling is found in many cancers and is closely related to cancer progression. As an important Notch receptor, abnormal Notch4 expression affects several tumor-cell behaviors, including stemness, the epithelial–mesenchymal transition, radio/chemoresistance and angiogenesis. In order to inhibit the oncogenic effects of Notch4 activation, several methods for targeting Notch4 signaling have been proposed. In this review, we summarize the known molecular mechanisms through which Notch4 affects cancer progression. Finally, we discuss potential Notch4-targeting therapeutic strategies as a reference for future research.

Keywords:

• Notch4 signaling
• cancer
• cancer stem cell
• epithelial–mesenchymal transition
• drug resistance
• molecular mechanism
• therapeutic perspective

Abbreviations

CSL, CBF-1 (RBPJ)/suppressor of hairless/Lag1; MAML, Mastermind-like protein; FBXW7, F-box and WD repeat domain containing; DTX3, Deltex E3 ubiquitin ligase 3; OS, Over Survival; DFS, Disease Free Survival; ALDH1, Aldehyde dehydrogenase7; Oct4, Organic cation/carnitine transporter4; Sox2, SRY-box transcription factor 2; NF-κB, Nuclear factor kappa B; DCAF13, DDB1 and CUL4 associated factor 13; Stat3, Signal transducer and activator of transcription 3; MMP, Matrix metallopeptidase; PKCα, Protein kinase C alpha; NCL, Nucleolin; NPM, Nucleophosmin; FBL, Fibrillarin; ER, Endoplasmic Reticulum; TRAIL, TNF-related apoptosis-inducing ligand; Akt, Serine/threonine kinase 1; ROS, Reactive oxygen species; mTOR, mechanistic target of rapamycin kinase; ERK1/2, Extracellular regulated MAP kinase1/2; VEGF, Vascular Endothelial Growth Factor.

Data Sharing Statement

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Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.