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The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer

ABSTRACT: DDX5 is a founding member of the DEAD-box RNA helicase family, which are a group of enzymes that regulate ribonucleoprotein (RNP) formation and function in every aspect of RNA metabolism. Our lab previously found that DDX5 is involved in energy homeostasis, a process altered in many cancers. Small cell lung cancer (SCLC) is an understudied cancer type that lacks effective treatment. Therefore, we investigated the roles of DDX5 in SCLC. We show here that DDX5 is overexpressed in SCLC cell lines. Depletion of DDX5 results in reduced growth and mitochondrial dysfunction in the chemoresistant SCLC cell line H69AR. The latter is evidenced by downregulation of genes involved in oxidative phosphorylation and impaired oxygen consumption,. Interestingly, depletion of DDX5 specifically leads to reduction of intracellular succinate, a TCA intermediate that serves as a direct electron donor to mitochondrial complex II. Taken together, we propose that the oncogenic role of DDX5 is at least in part manifested through upregulation of respiration to support the energy demands of cancer cells. This also suggests that defects in RNP remodeling are connected to energy metabolism and carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142024 | GEO | 2020/05/06

REPOSITORIES: GEO

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RIP-seq of DDX5 in rhabdomyosarcoma cells

Project description:Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. Here, we identified the DEAD box RNA helicase 5 (DDX5) as a potential therapeutic target to inhibit alveolar rhabdomyosarcoma (ARMS) growth. We show that DDX5 is overexpressed in alveolar RMS cells, demonstrating that its depletion drastically decreases ARMS viability and slows tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream the G9a/AKT survival signalling pathway, by modulating G9a protein stability

2022-08-22 | GSE175455 | GEO

DDX5 promotes prostate cancer progression and activates DNA repair pathway

Project description:The small heat shock protein Hsp27 has been long demonstrated as a major driver of Castration Resistant Prostate Cancer (CRPC) progression via an androgen receptor-independent pathway. In the light of identification of its molecular mechanisms, we found that the RNA helicase protein DDX5 was an interactor of Hsp27 and DDX5 expression was regulated by Hsp27 through its cytoprotective function. We showed that DDX5 was overexpressed in a large collection of human samples in aggressive PCs, especially CRPC. Here, we described the protein-protein interaction network of DDX5 which were identified in four human prostate cell lines (PNT1A, LNCaP, DU-145 and PC-3) representing different disease stages using immunoaffinity purification and quantitative mass spectrometry. The DDX5 interactome in CRPC cells was enriched in several functions (DNA damage response, translation, transcription, RNA stability, and DNA conformation changes) involved in disease progression. Furthermore, we found a new critical function of DDX5 in DNA damage repair in CRPC and validated the interaction of DDX5 with the DNA repair complex Ku70/Ku86 which plays a pivotal role in the NHEJ process. We also showed that DDX5 overexpression conferred resistance to DNA damage poisoners (such as irradiation and cisplatin) in CRPC, a feature that could lead to genome maintenance, tumor progression and treatment resistance.

2022-08-21 | PXD023252 | Pride

DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding

Project description:Hyaloid cartilage fibrosis is one of the important reasons for the poor prognosis of advanced osteoarthritis (OA), and is the main factor leading to joint stiffness and deformity. However, the mechanism of hyaline cartilage fibrosis remains largely unclear. Here we report that DDX5, one of the founding members of the DEAD-box RNA helicase family, was dramatically down-regulated in the degenerated articular cartilage of aged mice, and patients with OA, mouse destabilization of the medial meniscus (DMM) models，and cytokine (Interleukin (IL)-1β and tumor necrosis factor (TNF)-α) stimulation.In vitro and in vivo experimental findings that inhibition of DDX5 expression increases the fibrocartilage phenotype by reduction collagen type I (COL I) protein expression and up-regulate collagen type II (COL II) protein expression. In addition, The reduction of DDX5 aggravate cartilage degradation by induce the production of cartilage degrading enzymes. In addition, DDX5 induced exon 25 skip of FN1-AS and exon 14 skip of PLOD2-AS produced a transcript (termed FN1-AS1-SE25 and PLOD2-AS-SE14). The reduction in DDX5 results in an increase in the FN1-AS-WT and PLOD2-AS-WT variants.

2024-02-05 | GSE226983 | GEO

Effect of DDX5/DDX17 on genome-wide RNA Polymerase II distribution in SH-SY5Y cells

Project description:This project includes ChIP of total RNA pol II in human SH-SY5Y neuroblastoma cells following the joint depletion of RNA helicases DDX5 and DDX17 to determine the genome-wide effect of DDX5/DDX17 on RNA Pol II distribution.

2022-09-21 | GSE157850 | GEO

Identification of DDX5 target genes in spermatogonia

Project description:Sustained spermatogenesis in adult males and recovery of fertility following germ cell depletion are dependent on undifferentiated spermatogonia with self-renewal potential. Self-renewal of undifferentiated spermatogonia is dependent on a complex network of transcriptional and post-transcriptional regulatory factors. DDX5 is known to act as a transcriptional co-regulator in other systems through interactions with key transcription factors. Here, we performed ChIP-Seq to identify target genes of DDX5 in cultured undifferentiated spermatogonia in order to elucidate its role in maintenance of the male germline.

2019-04-02 | GSE110347 | GEO

DDX5 in colonic tumors

Project description:The Asp-Glu-Ala-Asp (DEAD)-box RNA binding protein, DDX5, is ubiquitously expressed in many cell types, yet its role in RNA metabolism and its downstream function in vivo has not been fully elucidated. In the intestine, DDX5 is highly expressed in the intestinal epithelial cell (IECs) and contributes to tumorigenesis. Here, we used a conditional mouse lines where DDX5 is knocked out in IECs upon Tamoxifen administration to uncover mechanisms underlying DDX5 functions in colon tumors.

2021-12-03 | GSE146014 | GEO

Expression signatures of human HeLa cells with RNAi targetting A1 hnRNP, FUS, H hnRNP and p68-DDX5

Project description:Transcription profiling of human HeLa cells (cervical cancer cell line) transfected with a plasmid expressing shRNAs cloned into the pSuper expression vector compared to emprty vector negative controls for transfection. Four different RNA interference treatments targetted: A1 hnRNP (HNRNPA1, Heterogeneous nuclear ribonucleoprotein A1); FUS (fusion gene, involved in t(12;16) in malignant liposarcoma); H hnRNP (HNRNPH1); and p68 helicase (DDX5, DEAD (Asp-Glu-Ala-Asp) box polypeptide 5). Keywords: genetic modification Five-condition experiment, where HNRNPA1, FUS, HNRNPH1 and DDX5 gene product levels were inhibited by siRNA transfection and compared to transfection with the negative control (scrambled siRNA). Biological replicates: 2 of each of the first three treatments and 3 of the treatment against DDX5, all independently grown and harvested. No technical replicates were performed.

2008-08-20 | E-GEOD-12058 | biostudies-arrayexpress

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Project description:Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly associated with the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation. Furthermore, we show that the DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal-like tumors than in non-basal-like tumors, including luminal A, luminal B, and HER2-enriched subtypes. Collectively, by combining proteomic and genomic approaches we reveal a role for DDX5 as a regulatory protein of Fra-1 signaling and suggest DDX5 as a potential therapeutic target for TNBC.

2019-09-03 | GSE112963 | GEO

RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, microRNA and splicing programs in cell differentiation

Project description:RNA helicases DDX5 and DDX17 are members of a large family of highly conserved proteins involved in gene expression regulation, although their in vivo targets and activities in biological processes like cell differentiation, that requires reprogramming of gene expression programs at multiple levels, are not well characterized. In this report, we uncovered a new mechanism by which DDX5 and DDX17 cooperate with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. We next observed that downregulation of DDX5 and DDX17 protein expression during epithelial to mesenchymal transdifferentiation and during myogenesis contributes to switching splicing programs during these processes. Remarkably, this downregulation is mediated by the production of microRNAs induced upon differentiation in a DDX5/DDX17-dependent manner. Since DDX5 and DDX17 also function as coregulators of master transcriptional regulators of differentiation, we propose to name these proteins M-bM-^@M-^\master orchestratorsM-bM-^@M-^] of differentiation, that dynamically orchestrate several layers of gene expression. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x siCTRLM-BM- ; 3 x si(DDX5-17) AND 6 samples of MCF10 cells exposed to different treatments were analyzed: 3 x siCTRLM-BM- ; 3 x si(DDX5-17)

2014-05-06 | E-GEOD-57281 | biostudies-arrayexpress

DDX5 RNA interactome in cultured T cells

Project description:RAR-related orphan receptor gamma (ROR t)-expressing regulatory T (ROR t+ Treg) cells play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part, by secreting the anti-inflammation cytokine interleukin 10 (IL-10). Here, we report that Hypoxia Induced Factor 1a (HIF1alpha) is the master transcription factor for *Il10* in ROR t+ Tregs. Interestingly, this critical anti-inflammatory pathway is negatively regulated by an RNA-binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1 and its downstream target gene *Il10* in ROR t+ Tregs. T cell specific *Ddx5* knockout (DDX5 T) mice have augmented ROR t+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1a restores enteropathy susceptibility in DDX5 T mice. The DDX5-HIF1 -IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.

2022-12-21 | GSE157259 | GEO

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