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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. Comparison of gene expression in large intestine of mice with or without reduced expression of DHX9.

ORGANISM(S): Mus musculus

SUBMITTER: Ola Larsson

PROVIDER: E-GEOD-76765 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Lee T T Paquet M M Larsson O O Pelletier J J

Oncogene 20160314 39

The NTP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, and microRNA-mediated control, DNA replication and maintenance of genomic stability. DHX9 has also been implicated in tumor cell maintenance and drug response. Here we report that inhibition of DHX9 expression is lethal to human cancer cell lines and murine Eμ-Myc lymphomas. Using a novel conditional shDHX9 mouse model, we demonstrate that sustained and ...[more]

PMID: 26973242

Similar Datasets

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.

2016-05-19 | GSE76765 | GEO

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

RNA helicase A is necessary for KIF1Bβ tumor suppression in neuroblastoma

2014-02-05 | GSE44585 | GEO

Targeted deletion of circadian clock gene Arntl in the nephron results in dysregulation of diverse metabolic pathways

Project description:The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question we performed transcriptomic analysis in mice with inducible and conditional ablation of the circadian clock system in the renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport. In parallel, kidneys from Bmal1lox/lox/Pax8-rtTA/LC1 mice exhibited a significant decrease in the NAD+/NADH ratio suggesting an increased anaerobic glycolysis and/or decreased mitochondrial function. In-depth analysis of two selected pathways revealed (i) a significant increase in plasma urea levels correlating with increased renal arginase 2 (Arg2) activity, hyperargininemia and increase of the kidney arginine content; (ii) a significantly increased plasma creatinine concentration and reduced capacity of the kidney to secrete anionic drugs (furosemide), paralleled by a ~80% decrease in the expression levels of organic anion transporter OAT3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at both the intra-renal and systemic levels and are involved in drug disposition. Mice with a specific ablation of the Arntl gene encoding BMAL1 in the renal tubular cells were compared to wild-type littermate at ZT4 and ZT16 (ZT â Zeitgeber time units; ZT0 is the time of light on and ZT12 is the time of light off).

2016-06-01 | E-GEOD-76838 | 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

Expression data from miR-203 induction in mouse skin

Project description:We identify numerous miR-203 in vivo targets that are highly enriched for the promotion of cell cycle and cell division. Importantly, individual targets including p63, Skp2 and Msi2 play distinct roles downstream of miR-203 to regulate the cell cycle and long-term proliferation. Together, our findings reveal rapid and widespread impact of miR-203 on the self-renewal program during the epidermal differentiation and provide mechanistic insights for the potent role of miR-203 where coordinated repression of multiple targets is required for the function of this miRNA. We used microarrays to measure transcriptome changes upon miR-203's induction in mouse skin and identified new targets of miR-203. We use two pairs of biological duplicates to perform the microarray analysis from the epidermal samples harvested from K14-rtTA/TRE-miR-203/K14-H2BGFP (DP) and TRE-miR-203/K14-H2BGFP (SP) littermates at P4, 24h after the Dox injection.

2013-03-14 | E-GEOD-45121 | biostudies-arrayexpress

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

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

Engineering ABT-737 Resistance in MYC-driven Lymphomas Identifies DHX9 as a Drug Response Modifier

Project description:Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241

2013-04-03 | E-GEOD-36938 | biostudies-arrayexpress

Expression data from miR-205 knockout in Hair Follicle Stem Cells (HFSCs) of mouse skin

Project description:We identified 201 genes that are consistently upregulated more than 20%, and 108 genes that are consistently downregulated more than 20% in the miR-205 KO samples in two sets of biological duplicates. We used microarrays to measure transcriptome changes upon knockout of miR-205 in hair follicle stem cells of mouse skin and identified new targets of miR-205. We isolated the HFSCs from WT and miR-205 KO skin at P4 and compare mRNA expression by microarray analysis

2013-08-20 | E-GEOD-46447 | biostudies-arrayexpress

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