DDX3X: structure, physiologic functions and cancer

Abstract

The DEAD-box helicase family member DDX3X (DBX, DDX3) functions in nearly all stages of RNA metabolism and participates in the progression of many diseases, including virus infection, inflammation, intellectual disabilities and cancer. Over two decades, many studies have gradually unveiled the role of DDX3X in tumorigenesis and tumour progression. In fact, DDX3X possesses numerous functions in cancer biology and is closely related to many well-known molecules. In this review, we describe the function of DDX3X in RNA metabolism, cellular stress response, innate immune response, metabolic stress response in pancreatic β cells and embryo development. Then, we focused on the role of DDX3X in cancer biology and systematically demonstrated its functions in various aspects of tumorigenesis and development. To provide a more intuitive understanding of the role of DDX3X in cancer, we summarized its functions and specific mechanisms in various types of cancer and presented its involvement in cancer-related signalling pathways.

Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

“…This led us to denote these RBPs as “multifunctional RBPs” - context-specific RBPs whose functional outcome depends on the set of mRNAs it targets. A key example appears to be the multifunctional RBP DDX3X (Mo et al, 2021; Soto-Rifo et al, 2012), whose abundance correlates significantly with the mRNA levels of 339 target genes (p adj = 2.83 × 10 −5 ; Glass’ Δ = 6.9) and the translational efficiency of 730 target genes (p adj = 5.25 × 10 −5 ; Glass’ ≤= 11.89), of which only 43 targets overlap between both sets ( Figure 3A and 3C ). The consequences of DDX3X binding for mRNA abundance (positive correlation) or TE (negative correlation) are opposite, though this is not the case for all multifunctional RBPs ( Figure S3B ).…”

“…Another example is DDX3X, a DEAD box helicase which can respond to stressors (e.g., viral infections (Yedavalli et al, 2004)) by switching subcellular compartments. DDX3X is involved in multiple processes required for RNA metabolism (Mo et al, 2021; Soto-Rifo et al, 2012), for which it uses its capacity to unwind complex and structured 5’ UTRs to promote translation initiation at selected subsets of mRNAs (Soto-Rifo et al, 2012; Shen & Pelletier, 2020; Calviello et al, 2020; Guenther et al, 2018). However, there is ongoing debate as to the precise roles of DDX3X and the mechanisms through which it regulates RNA metabolism (Shen & Pelletier, 2020), as it can act both as a repressor or activator of translation (Hilliker et al, 2011).…”

DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy

“…DDX3/Ded1 is one of the most widely studied DEAD-box RNA helicases. DDX3 regulates RNA metabolism, including transcription, pre-mRNA splicing, RNA export, and translation, which plays a critical role in many biological processes [ 20 ]. DDX3 also promotes phase separation when it interacts with ATP [ 41 ].…”

“…The role of DDX3 in oncogenesis is related to the regulation of cell growth, cell cycle, and cell survival. Increased DDX3 expression promotes cancer cell growth in medulloblastoma, colorectal, breast, prostate, and lung cancer [ 20 , 44 , 45 , 46 ], whereas depletion of DDX3 induces cell cycle arrest in the G1 phase in cancer cells of those cancers ( Table 1 ) [ 20 , 31 , 47 , 48 , 49 ]. Knockdown of DDX3 also inhibits cell cycle progression by blocking entry into the S phase.…”

“…The DEAD-box containing RNA helicases also play important roles in the pathophysiology of viral infection, aging, autosomal dominant polycystic kidney disease (ADPKD), neurological disorders, and cancer. First, the reduction of DDX3 is positively linked with hepatitis virus infection, especially HBV [ 20 ]. UAP56 or its paralog URH49 prevents the accumulation of dsRNA during influenza A virus infection via unwinding RNA [ 21 ].…”