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Tumor Cell Survival Dependence on the DExH-Box Helicase DHX9

ABSTRACT: The ATP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, microRNA-mediated control, DNA replication, and maintenance of genomic stability. DHX9 has also been implicated in maintenance of the tumorigenic process and in drug response. Here, we report that inhibition of DHX9 expression is lethal to multiple human and mouse cancer cell lines. In contrast, using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged suppression of DHX9 is well tolerated at the organismal level. Our results demonstrate a robust tolerance for DHX9 knockdown in non-transformed cells and supports the targeting of DHX9 as an effective and specific chemotherapeutic approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE76765 | GEO | 2016/05/19

SECONDARY ACCESSION(S): PRJNA308554

REPOSITORIES: GEO

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Tumor Cell Survival Dependence on the DExH-Box Helicase DHX9

Project description:The ATP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, microRNA-mediated control, DNA replication, and maintenance of genomic stability. DHX9 has also been implicated in maintenance of the tumorigenic process and in drug response. Here, we report that inhibition of DHX9 expression is lethal to multiple human and mouse cancer cell lines. In contrast, using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged suppression of DHX9 is well tolerated at the organismal level. Our results demonstrate a robust tolerance for DHX9 knockdown in non-transformed cells and supports the targeting of DHX9 as an effective and specific chemotherapeutic approach. Comparison of gene expression in large intestine of mice with or without reduced expression of DHX9.

2016-05-19 | E-GEOD-76765 | biostudies-arrayexpress

Bidirectional regulation of adenosine-to-inosine (A-to-I) RNA editing by DEAH box helicase 9 (DHX9) in cancer

Project description:Adenosine-to-inosine (A-to-I) RNA editing entails the enzymatic deamination of adenosines to inosines by adenosine deaminases acting on RNA (ADARs). Dysregulated A-to-I editing has been implicated in various diseases, including cancers. However, the precise factors governing the A-to-I editing and their physiopathological implications remain as a long-standing question. Herein, we unravel that DEAH box helicase 9 (DHX9), at least partially dependent of its helicase activity, functions as a bidirectional regulator of A-to-I editing in cancer cells. Intriguingly, the ADAR substrate specificity determines the opposing effects of DHX9 on editing as DHX9 silencing preferentially represses editing of ADAR1-specific substrates, whereas augments ADAR2-specific substrate editing. Analysis of 11 cancer types from The Cancer Genome Atlas (TCGA) reveals a striking overexpression of DHX9 in tumors. Further, tumorigenicity studies demonstrate a helicase-dependent oncogenic role of DHX9 in cancer development. In sum, DHX9 constitutes a bidirectional regulatory mode in A-to-I editing, which is in part responsible for the dysregulated editome profile in cancer.

2018-05-31 | GSE99789 | GEO

Tumor cell survival dependence on the DHX9 DExH-box helicase.

Project description: Not available

| S-EPMC5023453 | biostudies-literature

Dependence of p53-deficient cells on the DHX9 DExH-box helicase.

Project description: Not available

| S-EPMC5458177 | biostudies-other

DHX9 and NPM1 silencing RNA-seq

Project description:In our study, we valided DHX9 and NPM1 interact with KIMAT1, whereas DHX9 also interacts with HIF1A-As2. DHX9 is a highly conserved DEAD-box protein expressed in the nucleus and the cytoplasm, involved in many processes including transcriptional activation, miRNA biogenesis and tumor cell maintenance. NPM1 is predominantly localized in the nucleoplasm, where it associates with active RNA polymerase II and transcriptionally activates genes involved in cancer. We silenced DHX9 and NPM1 and performed RNA-seq to examine the dysregulated genes by DHX9 and NPM1.

2020-12-17 | GSE124626 | GEO

TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution

Project description:R-loops, which consist of a DNA/RNA hybrid and a displaced single-stranded DNA (ssDNA), are increasingly recognized as critical regulators of chromatin biology. R-loops are particularly enriched at gene promoters, where they play important roles in regulating gene expression. However, the molecular mechanisms that control promoter-associated R-loops remain unclear. The epigenetic “reader” Tudor domain-containing protein 3 (TDRD3), which recognizes methylarginine marks on histones and on the C-terminal domain of RNA polymerase II, was previously shown to recruit DNA topoisomerase 3B (TOP3B) to relax negatively supercoiled DNA and prevent R-loop formation. Here, we further characterize the function of TDRD3 in R-loop metabolism and introduce the DExH-box helicase 9 (DHX9) as a novel interaction partner of the TDRD3/TOP3B complex. TDRD3 directly interacts with DHX9 via its Tudor domain. This interaction is important for recruiting DHX9 to target gene promoters, where it resolves R-loops in a helicase activity-dependent manner to facilitate gene expression. Additionally, TDRD3 also stimulates the helicase activity of DHX9. This stimulation relies on the OB-fold of TDRD3, which likely binds the ssDNA in the R-loop structure. Thus, DHX9 functions together with TOP3B to suppress promoter-associated R-loops. Collectively, these findings reveal new functions of TDRD3 and provide important mechanistic insights into the regulation of R-loop metabolism.

2021-06-26 | GSE178905 | GEO

The DNA/RNA helicase DHX9 contributes to the transcriptional program of Androgen Receptor in prostate cancer.

Project description:Prostaste cancer (PC) is the most commonly diagnosed male malignancy and an important cause of mortality. Androgen signaling plays a key role in PC pathogenesis and the understanding of the mechanisms involved in the regulation of AR function might pave the ground for the development of more efficacious and long-lasting therapeutic strategies for PC patients. DNA/RNA helicases are emerging as important regulators of many cellular processes. Among them, DHX9 has been implicated in the control of genomic stability, transcription and DNA replication. To investigate the role of DHX9 in PC we perform RNA-sequencing analysis in androgen-sensitive LNCaP cells affects upon DHX9 silencing.

2022-05-25 | GSE195916 | GEO

Structural basis of RNA-induced autoregulation of the DExH-type RNA helicase maleless

Project description:RNA unwinding by DExH-type helicases underlies most RNA metabolism and function. It remains unresolved if and how the basic unwinding reaction of helicases is regulated by auxiliary domains. We explored the interplay between the RecA and auxiliary domains of the RNA helicase maleless (MLE) from Drosophila, using a suite of structural and functional studies. We discovered that MLE exists in a dsRNA bound open conformation and the auxiliary dsRBD2 domain aligns the substrate RNA with the accessible helicase tunnel. In an ATP-dependent manner, dsRBD2 associates with the helicase module, leading to tunnel closure around ssRNA. Furthermore, our structures provide a rationale for blunt ended dsRNA unwinding and 3’-5’ translocation by MLE. Structure-based MLE mutations confirm the functional relevance of our model for RNA unwinding. Our findings contribute to our understanding of fundamental mechanics of auxiliary domains in DExH helicase MLE which serves as model for its human ortholog and potentially therapeutic target, DHX9/RHA.

2023-11-27 | PXD045725 | Pride

Human Nup98 regulates the localization and activity of DExH/D-box helicase DHX9.

Project description: Not available

| S-EPMC5338925 | biostudies-literature

RNA helicase A is necessary for KIF1Bβ tumor suppression in neuroblastoma

Project description:During development neuronal progenitors compete for growth factors such as nerve growth factor NGF and require the prolyl hydroxylase EglN3 and the kinesin KIF1Bβ for developmental apoptosis. Inherited KIF1Bβ loss-of-function mutations in neuroblastomas and pheochromocytomas implicate KIF1Bβ as a 1p36.2 tumor suppressor, however the mechanism of tumor suppression is unknown. We found that KIF1Bβ interacts with the RNA helicase A (DHX9) resulting in DHX9 nuclear accumulation to regulate apoptosis. KIF1Bβ-dependent DHX9 nuclear localization leads to transcription of the apoptotic target XIAP-associated factor 1. DHX9 is induced when NGF is limiting and required for apoptosis in cells deprived of NGF. NB1 cells were transduced to incorporate shRNA against DHX9 or a scrambled control, and transfected with a KIF1Bβ expression vector or control, then transfected cells were isolated and lysed after 48h.

2014-02-05 | E-GEOD-44585 | biostudies-arrayexpress

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