Multifunctional DDX3: dual roles in various cancer development and its related signaling pathways

Abstract

DEAD-box RNA helicase 3 (DDX3) is a highly conserved family member of DEAD-box protein, which is a cluster of ATP-dependent and the largest family of RNA helicase. DEAD-box family is characterized by the regulation of ATPase and helicase activities, the modulation of RNA metabolism, and the actors of RNA binding proteins or molecular chaperones to interact with other proteins or RNA. For DDX3, it exerts its multifaceted roles in viral manipulation, stress response, hypoxia, radiation response and apoptosis, and is closely related to cancer development and progression. DDX3 has dual roles in different cancer types and can act as either an oncogene or tumor suppressor gene during cancer progression. In the present review, we mainly provide an overview of current knowledge on dual roles of DDX3 in various types of cancer, including breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, oral squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme and gallbladder carcinoma, and illustrate the regulatory mechanisms for leading these two controversial biological effects. Furthermore, we summarize the essential signaling pathways that DDX3 participated, especially the Wnt/β-catenin signaling and EMT related signaling (TGF-β, Notch, Hedgehog pathways), which are crucial to DDX3 mediated cancer metastasis process. Thoroughly exploring the dual roles of DDX3 in cancer development and the essential signaling pathways it involved, it will help us open new perspectives to develop novel promising targets to elevate therapeutic effects and facilitate the "Personalized medicine" or "Precision medicine" to come into clinic.

Keywords: DDX3; EMT related pathway; Wnt/β-catenin pathway; cancer; oncogene; tumor suppressor gene.

Figure 1

The role of DDX3 in breast cancer. Under hypoxic conditions, hypoxia inducible factor-1α (HIF-1α) could bind to the putative HIF-1 responsive elements (HRE) located in the promoter region of DDX3 gene, and transcriptionally activate the expression of DDX3. Meanwhile, the expression of DDX3 was correlated with over-expression of HIF-1α and its downstream genes CAIX, GLUT1, and several hypoxia related genes, including EGFR, HER2, ERα, c-Met and FOXO4. Moreover, DDX3 could repress E-cadherin expression and induce the Epithelial-mesenchymal transition (EMT) process to facilitate breast cancer metastasis. A novel DDX3 inhibitor, which a ring-expanded nucleoside analogue (REN), named for NZ51, could inhibit the ATP dependent helicase activity of DDX3. During DNA damage response, DDX3 could associate with p53, promote the accumulation of p53 in the nucleus, and activate its downstream target p21 expression, so as to modulate DNA damage induced apoptosis in cells expressed functional wild-type p53. However, in cells expressed non-functional or mutant p53, DDX3 otherwise inhibited the apoptosis process.

Figure 2

The mechanism of DDX3 acting as a tumor suppressor. The transcription of DDX3 can be regulated by p53, and the expression level of DDX3 is dependent on p53 status. Meanwhile, through interacting and cooperating with Sp1, DDX3 could increase Sp1 binding affinity onto the p21 promoter region and up-regulate the promoter activity of p21 so as to exert its tumor suppressive roles on cell cycle and apoptosis. Moreover, DDX3 could also increase Sp1 binding activity to the MDM2 promoter, and promote the MDM2 transcription process. Consequently, the up-regulation of MDM2 leads to the suppression of Slug, which negatively regulates the expression of E-cadherin. As a result, through increasing MDM2-mediated Slug suppression, DDX3 can act as a tumor suppressor by elevating the E-cadherin expression and impeding the Epithelial-mesenchymal transition (EMT) progression.

Figure 3

DDX3 is involved in Wnt/β-catenin pathway. When Wnt/β-catenin signaling is activated, the Wnt ligands bind to the Frizzled receptor and the co-receptor lipoprotein receptor related protein 5/6 (LRP5/6) in the membrane. Then, the Dishevelled (Dvl) gathers the cytoplasmic Axin and GSK3β into the membrane, and facilitate the activated β-catenin translocating from cytoplasm to nucleus. The nucleus β-catenin could interact with two major transcription factors, the T-cell factor (TCF) and lymphocyte enhancer factor (LEF), accompanied with several transcription co-activators, BCL9, CBP, p300, Pygo, to regulate multiple genes transcription. These downstream target genes mainly include Snail1, MMP7, PAI1, RAS, and Fibronectin. For the role of DDX3 in Wnt/β-catenin signaling, DDX3 could directly bind to CK1ε, stimulate its kinase activity and further promote the phosphorylation of the scaffold protein Dvl, so as to facilitate β-catenin translocating into the nucleus. Moreover, up-regulation of DDX3 expression contributes to the induction of TCF reporter activity and the elevation of mRNA expression levels of TCF-regulated downstream genes, such as c-MYC, AXIN2, CCND1 and BIRC5A.