DDX5 and DDX17-multifaceted proteins in the regulation of tumorigenesis and tumor progression

Abstract

DEAD-box (DDX)5 and DDX17, which belong to the DEAD-box RNA helicase family, are nuclear and cytoplasmic shuttle proteins. These proteins are expressed in most tissues and cells and participate in the regulation of normal physiological functions; their abnormal expression is closely related to tumorigenesis and tumor progression. DDX5/DDX17 participate in almost all processes of RNA metabolism, such as the alternative splicing of mRNA, biogenesis of microRNAs (miRNAs) and ribosomes, degradation of mRNA, interaction with long noncoding RNAs (lncRNAs) and coregulation of transcriptional activity. Moreover, different posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, endow DDX5/DDX17 with different functions in tumorigenesis and tumor progression. Indeed, DDX5 and DDX17 also interact with multiple key tumor-promoting molecules and participate in tumorigenesis and tumor progression signaling pathways. When DDX5/DDX17 expression or their posttranslational modification is dysregulated, the normal cellular signaling network collapses, leading to many pathological states, including tumorigenesis and tumor development. This review mainly discusses the molecular structure features and biological functions of DDX5/DDX17 and their effects on tumorigenesis and tumor progression, as well as their potential clinical application for tumor treatment.

Keywords: DDX17; DDX5; RNA transcription regulation; posttranslational modification; tumor progression; tumorigenesis.

Figure 1

DDX5 and DDX17 are involved in RNA metabolism. DDX5/DDX17 are involved in ribosome synthesis, microRNA (miRNA) biosynthesis, regulation of mRNA alternative splicing, and the promotion or inhibition of mRNA transcription. DDX5 is also involved in nonsense-mediated mRNA decay (NMD), unwinding of R-loops and G-quadruplexes.

Figure 2

Posttranslational modifications and functions of DDX5/DDX17. DDX5 can undergo phosphorylation, acetylation, methylation, ubiquitination, sumoylation, O-GlcNAcylation, etc. DDX17 can undergo acetylation, ubiquitination, sumoylaton, etc. Different posttranslational modifications endow DDX5/DDX17 with diverse biological functions, and the same modification at different sites leads to different functional outcomes.

Figure 3

DDX5/DDX17 play an extremely important role in the p53 signaling pathway. DDX5/DDX17 are coreguulators of p53, and DDX5 selectively regulates p53 mediation of growth arrest or apoptosis; DDX5 positively regulates the expression of p53 by inhibiting Δ133p53. In contrast, DDX17 negatively regulates p53 expression by inducing Mdm2 expression.

Figure 4

DDX5/DDX17 participate in the β-catenin signaling pathway to promote tumorigenesis and tumor progression. In the cytoplasm, DDX5/DDX17 dissociate β-catenin from the complex and transport it to the nucleus to promote the transcription of β-catenin target genes (c-Jun, c-Myc, cyclin D1, TCF4, AKT, etc.), which then participate in tumorigenesis and tumor progression.

Figure 5

DDX5/DDX17 are involved in tumor progression through NF-κB and Notch signaling pathways. In the NF-κB signaling pathway(i), DDX5 promotes the release of the inhibitory subunit IκBα, induces nuclear translocation of the p50 subunit, and in directly phosphorylates the p65 subunit, thereby promoting the transcription of NF-κB target genes. DDX17 is involved in alternative splicing of p65 subunit target genes such as CD44. In the Notch signaling pathway(ii), DDX5 binds MAML1 and is recruited to the Notch We would like to delete the entire glossary section. Please see below. transcription complex to promote the transcription of target genes.

Figure 6

DDX17 participates in the YAP signaling pathway to increase the stemness of cancer stem-like cells and to promote tumorigenesis and tumor progression. In tumor cells, that is, at low density, YAP is located in the nucleus and serves as a transcription-assisted activator to promote cell proliferation. Under hypoxic conditions, K190 on DDX17 undergoes K63 ubiquitination by the E3 ligase HectH9. YAP binds to and isolates ubiquitinated DDX17, dissociating it from the Drosha-DGCR8 complex to block the biosynthesis of antitumor stem microRNAs (miRNAs). Meanwhile, ubiquitinated DDX17 forms a YAP-DDX17-p300 complex, leading to the acetylation of histone 3 lysine 56 (H3K56) to activate cancer-related gene transcription, resulting in increased stemness of cancer stem-like cells.