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Review
. 2023 Oct 27:13:1278282.
doi: 10.3389/fonc.2023.1278282. eCollection 2023.

Role and therapeutic potential of DEAD-box RNA helicase family in colorectal cancer

Bichun Zheng  1 , Xudong Chen  1 , Qiaoyun Ling  1 , Quan Cheng  1 , Shaoshun Ye  1
Affiliations
Review

Role and therapeutic potential of DEAD-box RNA helicase family in colorectal cancer

Bichun Zheng et al. Front Oncol. .

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed and the second cancer-related death worldwide, leading to more than 0.9 million deaths every year. Unfortunately, this disease is changing rapidly to a younger age, and in a more advanced stage when diagnosed. The DEAD-box RNA helicase proteins are the largest family of RNA helicases so far. They regulate almost every aspect of RNA physiological processes, including RNA transcription, editing, splicing and transport. Aberrant expression and critical roles of the DEAD-box RNA helicase proteins have been found in CRC. In this review, we first summarize the protein structure, cellular distribution, and diverse biological functions of DEAD-box RNA helicases. Then, we discuss the distinct roles of DEAD-box RNA helicase family in CRC and describe the cellular mechanism of actions based on recent studies, with an aim to provide future strategies for the treatment of CRC.

Keywords: DEAD-box RNA helicases; cellular distribution; colorectal cancer; mechanism; physiological role.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the structural features of DEAD-box RNA helicase family proteins. The DEAD-box RNA helicase family proteins contain a conserved helicase core and variable N- and C-terminus regions (grey). The conserved helicase core consists of two RecA-like domains (domain 1 and domain 2), which contain 7 and 5 conserved sequence motifs, respectively. Among these motifs, the motifs Q, I, II, and VI are involved in ATP binding and hydrolysis (red), the motifs of Ia, Ib, Ic, IV, IVa, and V are participated in RNA recognition (blue), and the motifs of III and Va are involved in the coordination between RNA and ATP binding (green).
Figure 2
Figure 2
Schematic diagram of the DDX5 (also known as p68) and DDX17 (also known as p72) in CRC development. PIAS1 interacted with p68 and enhanced p68 sumoylation by SUMO-2. Sumoylated p68 increased the transcriptional repression activity of p68 and suppressed its ability to function as a coactivator of p53 by interacting with HDAC1. p68 protein could be modified by O-GlcNAcylation (G) to maintain its protein stability. p68 not only acted as a transcriptional co-activator of β-catenin, it also occupied AKT promoter with β-catenin as well as NF-κB and cooperated with them to potentiate AKT transcription, leading to the increases of AKT mRNA and protein levels, and consequent activation of Akt/mTOR pathway and inhibition of FOXO3a pathway. Moreover, p68 along with β-catenin occupied TCF4/LEF binding sites on the promoter of endogenous CHIP and FOXM1 and modulated their transcription. p68 could also mediate the mRNA stabilization of PHGDH, leading to nucleotide metabolic reprogramming to promote CRC progression and chemoresistance. p68 expression can be regulated by PUM1 and many non-coding RNAs, including lncRNA NEAT1 and SNHG14, and circular RNA EGFR. p68 and p72 formed complexes with β-catenin and augmented β-catenin to activate the transcription of proto-oncogenes, including c-Myc, cyclin D1, c-jun, and fra-1, and suppress the transcription of the cell cycle inhibitor p21(WAF1/CIP1), which is mediated via c-Myc. p72 downregulated miR-149-3p expression, leading to the upregulation of its target CYBRD1 expression to promote the metastasis and EMT of CRC cells. HDAC1, histone deacetylase 1; NF-κB, nuclear factor-κB; PUM1, Pumilio RNA-binding family member 1; VEGF, vascular endothelial growth factor; TCF4, transcription factor 4.
Figure 3
Figure 3
The mechanism of DDX6 in CRC. DDX6 could activate the canonical Wnt/β-catenin pathway to promote the proliferation and inhibit the apoptosis of CRC cells. DDX6 also affect the apoptosis of CRC cells via upregulating PKM1 expression. Additionally, DDX6 facilitated c-Myc translation and contributed to the Warburg effect through the DDX6/c-Myc/PTB1 positive-feedback circuit. DDX6 was a target of miR-124. And miR-124 also targeted PTB1 and regulated the Warburg effect by switching the expression of PKM isoform from PKM2 to PKM1.
Figure 4
Figure 4
The mechanism of DDX21 in CRC. DDX21 promoted CRC proliferation not only via interacting with CDC5L to regulate cyclin B and CDC2, but also by directly recruiting WDR5 to activate CDK1 gene expression through enhancing H3K4me3 on its promoter. DDX21 has a strong IDR, which makes it form phase-separated condensates. Phase separation of DDX21 facilitated CRC metastasis via directly targeting on MCM5 to induce its expression and subsequently leading to the activation of EMT pathway. LncRNA ZFAS1 directly recruited DDX21 protein and positively regulated its expression, and then affected POLR1B expression, resulting in promotion of CRC cell growth, migration and invasion. CDC5L, cell division cycle 5-like; H3K4me3, trimethylation of histone H3 on Lys 4; IDR, intrinsically disordered region.
Figure 5
Figure 5
The mechanism of DDX27 in CRC. DDX27 promoted the proliferation, migration, invasion and EMT of CRC cells via directly interacting with NPM1 in the nucleus. Their binding promoted the interaction between nuclear NPM1 and NF-κB p65 to increase the binding activity of p65 to promoters of NF-кB target genes (such as BIRC3, CCL20, CXCL3, NFKBIA, TNF, and TNFAIP3), leading to increases of their transcription. DDX27 could promote CRC stemness and chemoresistance. During these processes, DDX27 expression was positively regulated by circ_RNF13 via TRIM24-mediated transcriptional regulation. And circ_RNF13 stabilized TRIM24 via suppressing FBXW7-mediated TRIM24 degradation. NPM1, nucleophosmin.
Figure 6
Figure 6
The mechanism of DDX39B in CRC. DDX39B upregulated the expression of FUT3 by regulating mRNA splicing and export, followed by the fucosylation of TGFβR-I and activation of the TGF-β/SMAD signaling pathway to facilitate the metastasis of CRC. Moreover, DDX39B bound directly to CDK6/CCND1 pre-mRNA and subsequently promoted the pre-mRNA splicing and export, leading to the increases of their expression levels, which contributed to CRC cell proliferation. Additionally, DDX39B directly bound to PKM2 to increased its stability by competitively suppressing STUB1-mediated PKM2 ubiquitination and degradation, and then accelerated the nuclear translocation of PKM2 by recruiting importin α5 in an ERK1/2-mediated phosphorylation-independent manner. Nuclear PKM2 promoted the expression of oncogenes and glycolytic genes (such as c-Myc, GLUT1, LDHA, Cyclin D1, and MEK5) to induce CRC cell proliferation and metastasis. DDX39B expression could be induced by Sp1 transcription factor through direct binding.
Figure 7
Figure 7
The mechanism of EIF4A3 in CRC. The binding of EIF4A3 and lncRNA H19 obstructed the recruitment of EIF4A3 to the mRNA of cyclin E1, cyclin D1, and CDK4, resulted in their upregulation. The binding between EIF4A3 and circ-SIRT1 decreased the abundance of EIF4A3 at the mRNAs of N-cadherin and Vimentin, leading to the suppression of these mRNAs degradation. EIF4A3 could bind to the flanking sequences of circ_0084615, a circRNA derived from ASPH, and positively regulated circ_0084615 expression. Circ_0084615 functioned in CRC via miR-599/ONECUT2 pathway. While EIF4A3 could inhibit the cyclization of circPTEN1 after binding to its flanking sequences. CircPTEN1 suppressed CRC metastasis via inhibition of TGF-β/Smad-mediated EMT. CAF secreted exosomes cricN4BP2L2 could bind to EIF4A3 and positively regulate its expression, and subsequently caused the activation of PI3K/AKT/mTOR axis in CRC cells, which promoted CRC cells stemness and oxaliplatin resistance. ASPH, aspartate beta-hydroxylase; CAF, cancer-associated fibroblasts.
Figure 8
Figure 8
Dual role of DDX3X and DDX58 in CRC. Studies demonstrated that DDX3X acted as a tumor promoter in CRC through activating the Wnt/β-catenin/CK1ϵ/Dvl2 pathway and YAP1/SIX2 axis, or enhancing KRAS transcription and subsequently activating the β-catenin/ZEB1 axis via the ERK/PTEN/AKT signaling pathway. Other studies revealed that DDX3X acted as a tumor suppressor by inhibiting E-cadherin and activating β-catenin signaling via suppressing the MAPK pathway. About DDX58, some studies showed that it acted as a tumor promoter in CRC through activation of the NF-κB pathway and circRIG-I signaling, or through restraining CD8+ T cell survival and cytotoxicity by restricting STAT5 activation. Other study found that DDX58 functioned as a tumor suppressor by interacting with STAT3 and inhibiting the STAT3/CSE signaling. ZEB1, zinc finger E-box binding homeobox 1.
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