Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy

Abstract

DEAD/H-box helicases are implicated in virtually every aspect of RNA metabolism, including transcription, pre-mRNA splicing, ribosomes biogenesis, nuclear export, translation initiation, RNA degradation, and mRNA editing. Most of these helicases are upregulated in various cancers and mutations in some of them are associated with several malignancies. Lately, synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, where genetic interactions of cancer-related genes are exploited as therapeutic targets, are emerging as a leading area of cancer research. Several DEAD/H-box helicases, including DDX3, DDX9 (Dbp9), DDX10 (Dbp4), DDX11 (ChlR1), and DDX41 (Sacy-1), have been subjected to SL analyses in humans and different model organisms. It remains to be explored whether SDL can be utilized to identity druggable targets in DEAD/H-box helicase overexpressing cancers. In this review, we analyze gene expression data of a subset of DEAD/H-box helicases in multiple cancer types and discuss how their SL/SDL interactions can be used for therapeutic purposes. We also summarize the latest developments in clinical applications, apart from discussing some of the challenges in drug discovery in the context of targeting DEAD/H-box helicases.

Keywords: DEAD/H-box helicase; cancer; drug development; synthetic dosage lethality; synthetic lethality; therapeutic target.

Figure 1

General structure and functions of DEAD/H-box helicases. (A) The N-terminal and C-terminal regions are involved in protein-protein interactions. Motifs Q, I, II, and VI are involved in ATP binding and hydrolysis; motifs III, V, and VI in RNA unwinding; motifs Ia, Ib, Ic, IV, IVa, and V in RNA binding and annealing; motifs III and Va in coordination between ATP and RNA binding. (B) Roles of DEAD/H-box RNA helicases in the central dogma pathway. Only the most studied top two to four helicases are shown in each catalogue. Some roles outside of the central dogma are not shown. Related references are shown as superscripts.

Figure 2

Heatmap of DEAD/H-box helicases expression in 24 different cancers and normal tissues from TCGA patient data. The blue color represents that they are significantly lost in tumor samples compared to normal samples, red color represents that they are significantly overexpressed in tumor samples compared to normal samples, and grey means no significant difference between normal and tumor samples. Cancer type abbreviations used are: BRCA, Breast invasive carcinoma; COAD, Colon adenocarcinoma; LUSC, Lung squamous cell carcinoma; LUAD, Liver hepatocellular carcinoma; HNSC, Head and neck squamous cell carcinoma; STAD, Stomach adenocarcinoma; LIHC, Liver hepatocellular carcinoma; KIRP, Kidney renal papillary cell carcinoma; UCEC, Uterine corpus endometrial carcinoma; KIRC, Kidney renal clear cell carcinoma; KICH, Kidney Chromophobe; BLCA, Bladder urothelial carcinoma; CHOL, Cholangiocarcinoma; GBM, Glioblastoma multiforme; ESCA, Esophageal carcinoma; READ, Rectum adenocarcinoma; PRAD, Prostate adenocarcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; PCPG, Pheochromocytoma and paraganglioma; SARC, Sarcoma; PAAD, Pancreatic adenocarcinoma; SKCM, Skin cutaneous melanoma; THYM, Thymoma; THCA, Thyroid carcinoma. BAT1 is DDX39B and EIF4A1 is DDX2.

Figure 3

Schematic illustration of synthetic lethality (A) and synthetic dosage lethality (B) for DEAD/H-box helicases. Cross on a gene stands for mutation or inhibition.