The enigmatic helicase DHX9 and its association with the hallmarks of cancer

Abstract

Much interest has been expended lately in characterizing the association between DExH-Box helicase 9 (DHX9) dysregulation and malignant development, however, the enigmatic nature of DHX9 has caused conflict as to whether it regularly functions as an oncogene or tumor suppressor. The impact of DHX9 on malignancy appears to be cell-type specific, dependent upon the availability of binding partners and activation of inter-connected signaling pathways. Realization of DHX9's pivotal role in the development of several hallmarks of cancer has boosted the enzyme's potential as a cancer biomarker and therapeutic target, opening up novel avenues for exploring DHX9 in precision medicine applications. Our review discusses the ascribed functions of DHX9 in cancer, explores its enigmatic nature and potential as an antineoplastic target.

Keywords: DHX9; biomarker; cancer; helicase; medicine; target; tumor.

Figure 1.. Human DExH-Box helicase 9 protein structure, domains and motifs.

The entire protein is 1280 amino acids in length, with amino acid positions of domains and motifs shown as determined by UNIPROT. The helicase core domain consists of two distinct regions – the helicase ATP-binding domain (domain 1) in which the DExH motif is located, and the helicase C-terminal (domain 2). dsRBD I/II: Double-stranded RNA-binding domain I/II; Domain 1: Helicase ATP-binding domain; Domain 2: Helicase C-terminal domain; HA2: Helicase-associated domain 2; MTAD: Minimal transactivation domain; OB-fold: Oligonucleotide- or oligosaccharide-binding fold; RGG: Repeated arginine and glycine-glycine.

Figure 2.. DExH-Box helicase 9-mediated R-loop resolution in the maintenance of genomic stability, transcription and DNA replication.

(A) DHX9 associates with RNA Pol II and functions in the resolution of R-loops by unwinding nascent RNA. The unwound mRNA is then bound by splicing factors to prevent strand invasion and thus transcription continues efficiently. In the absence of splicing factors, the unwound mRNA can invade duplex DNA to re-form an RNA/DNA hybrid and generate an R-loop. (B) DHX9-BRCA1 interaction recruits BRCA1 to sites of transcription/replication conflicts. Upon collision of transcription and replication machinery, DHX9 functions in R-loop resolution while BRCA1 functions in protection and repair of stalled replication forks and associated DNA damage. Upon removal of R-loops, RNA Pol II can dissociate allowing efficient DNA replication. (C) DHX9 recruits BRCA1 to sites of dsDNA breaks. Formation of R-loops near double-stranded break sites recruits BRCA1 where it interacts with SETX in order to mediate end resection and initiate homologous recombination, resulting in repaired DNA and maintenance of genomic stability. DHX9: DExH-Box helicase 9; DNA Pol: DNA polymerase; mRNA: Messenger RNA; RNA Pol II: RNA polymerase II; SETX: Senataxin.

Figure 3.. DExH-Box helicase 9 participates in the transcription of both cyclin D1 and p16^INK4A, exhibiting both oncogenic and tumor suppressive functions.

(A) Following EGF-stimulated nuclear translocation of EGFR, DHX9 facilitates EGFR-mediated cyclin D1 transcription. (B) DHX9 interacts with EWS-FLI1 in Ewing sarcoma cells, promoting EWS-FLI1-mediated cyclin D1 transcription. (C) DHX9 binds to the p16^INK4a promoter, functioning as a transcriptional coactivator to induce p16 transcriptional. Cyclin D1 binds CDK4/6 to induce dissociation of Rb and E2F, stimulating G1/S transition to promote replicative immortality. P16^INK4A functions as a tumor suppressor by inhibiting the cyclin D1-CDK4/6 complex, thus allowing Rb to inhibit E2F-mediated transcription of genes promoting G1/S transition. In cancer cells, the interaction between DHX9 and p16^INK4A is often suppressed, thus diminishing its tumor suppressive abilities. CDK4/6: Cyclin-dependent kinase-4/-6; DHX9: DExH-Box helicase 9; EGFR: EGF receptor; p16: p16INK4a; Rb: Retinoblastoma protein.