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

ABSTRACT: DEAD-box helicase 5 (DDX5) is a founding member of the DEAD-box RNA helicase family, a group of enzymes that regulate ribonucleoprotein formation and function in every aspect of RNA metabolism, ranging from synthesis to decay. Our laboratory previously found that DDX5 is involved in energy homeostasis, a process that is altered in many cancers. Small cell lung cancer (SCLC) is an understudied cancer type for which effective treatments are currently unavailable. Using an array of methods, including short hairpin RNA-mediated gene silencing, RNA and ChIP sequencing analyses, and metabolite profiling, we show here that DDX5 is overexpressed in SCLC cell lines and that its down-regulation results in various metabolic and cellular alterations. Depletion of DDX5 resulted in reduced growth and mitochondrial dysfunction in the chemoresistant SCLC cell line H69AR. The latter was evidenced by down-regulation of genes involved in oxidative phosphorylation and by impaired oxygen consumption. Interestingly, DDX5 depletion specifically reduced intracellular succinate, a TCA cycle intermediate that serves as a direct electron donor to mitochondrial complex II. We propose that the oncogenic role of DDX5, at least in part, manifests as up-regulation of respiration supporting the energy demands of cancer cells.

SUBMITTER: Xing Z

PROVIDER: S-EPMC7335798 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

2020-05-06 | GSE142024 | GEO

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

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

| PRJNA595593 | ENA

Multiple functions of the DEAD-box RNA helicase, DDX5 (p68), make DDX5 a superior oncogenic biomarker and target for targeted cancer therapy.

Project description:DDX5 (p68) is a well-known multifunctional DEAD-box RNA helicase and a transcription cofactor. Since its initial discovery more than three decades ago, DDX5 is gradually recognized as a potential biomarker and target for the treatment of various cancer types. Studies over the years significantly expanded our understanding of the functional diversity of DDX5 in various cancer types and extended our knowledge of its Mechanism of Action (MOA). This provides a rationale for the development of novel cancer therapeutics by using DDX5 as a biomarker and a therapeutic target. However, while most of the published studies have found DDX5 to be an oncogenic target and a cancer treatment-resistant biomarker, a few studies have reported that in certain scenarios, DDX5 may act as a tumor suppressor. After careful review of all the available relevant studies in the literature, we found that the multiple functions of DDX5 make it both a superior independent oncogenic biomarker and target for targeted cancer therapy. In this article, we will summarize the relevant studies on DDX5 in literature with a careful analysis and discussion of any inconsistencies encountered, and then provide our conclusions with respect to understanding the MOA of FL118, a novel small molecule. We hope that such a review will stimulate further discussion on this topic and assist in developing better strategies to treat cancer by using DDX5 as both an oncogenic biomarker and therapeutic target.

| S-EPMC8569338 | biostudies-literature

New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats.

Project description:Myotonic Dystrophy type I (DM1) is caused by an abnormal expansion of CTG triplets in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene, leading to the aggregation of the mutant transcript in nuclear RNA foci. The expanded mutant transcript promotes the sequestration of the MBNL1 splicing factor, resulting in the misregulation of a subset of alternative splicing events. In this study, we identify the DEAD-box RNA helicase p68 (DDX5) in complexes assembled onto in vitro-transcribed CUG repeats. We showed that p68 colocalized with RNA foci in cells expressing the 3'UTR of the DMPK gene containing expanded CTG repeats. We found that p68 increased MBNL1 binding onto pathological repeats and the stem-loop structure regulatory element within the cardiac Troponin T (TNNT2) pre-mRNA, splicing of which is misregulated in DM1. Mutations in the helicase core of p68 prevented both the stimulatory effect of the protein on MBNL1 binding and the colocalization of p68 with CUG repeats, suggesting that remodeling of RNA secondary structure by p68 facilitates MBNL1 binding. We also found that the competence of p68 for regulating TNNT2 exon 5 inclusion depended on the integrity of MBNL1 binding sites. We propose that p68 acts as a modifier of MBNL1 activity on splicing targets and pathogenic RNA.

| S-EPMC3326330 | biostudies-literature

RNA helicase DDX5 regulates microRNA expression and contributes to cytoskeletal reorganization in basal breast cancer cells.

Project description:RNA helicase DDX5 (also p68) is involved in all aspects of RNA metabolism and serves as a transcriptional coregulator, but its functional role in breast cancer remains elusive. Here, we report an integrative biology study of DDX5 in breast cancer, encompassing quantitative proteomics, global MicroRNA profiling, and detailed biochemical characterization of cell lines and human tissues. We showed that protein expression of DDX5 increased progressively from the luminal to basal breast cancer cell lines, and correlated positively with that of CD44 in the basal subtypes. Through immunohistochemistry analyses of tissue microarrays containing over 200 invasive human ductal carcinomas, we observed that DDX5 was up-regulated in the majority of malignant tissues, and its expression correlated strongly with those of Ki67 and EGFR in the triple-negative tumors. We demonstrated that DDX5 regulated a subset of MicroRNAs including miR-21 and miR-182 in basal breast cancer cells. Knockdown of DDX5 resulted in reorganization of actin cytoskeleton and reduction of cellular proliferation. The effects were accompanied by up-regulation of tumor suppressor PDCD4 (a known miR-21 target); as well as up-regulation of cofilin and profilin, two key proteins involved in actin polymerization and cytoskeleton maintenance, as a consequence of miR-182 down-regulation. Treatment with miR-182 inhibitors resulted in morphologic phenotypes resembling those induced by DDX5 knockdown. Using bioinformatics tools for pathway and network analyses, we confirmed that the network for regulation of actin cytoskeleton was predominantly enriched for the predicted downstream targets of miR-182. Our results reveal a new functional role of DDX5 in breast cancer via the DDX5?miR-182?actin cytoskeleton pathway, and suggest the potential clinical utility of DDX5 and its downstream MicroRNAs in the theranostics of breast cancer.

| S-EPMC3277758 | biostudies-literature

RNA helicase DDX5-induced circPHF14 promotes gastric cancer cell progression

Project description:To identify whether the expression of DDX5 was linked to circular RNAs splicing processes, we transfected AGS cell with FLAG-DDX5 or FLAG-tagged empty vector (negative control, NC), and analyzed the differentially expressed circRNAs

2023-04-26 | GSE207636 | GEO

The DEAD-box RNA helicase 51 controls non-small cell lung cancer proliferation by regulating cell cycle progression via multiple pathways.

Project description:The genetic regulation of cell cycle progression and cell proliferation plays a role in the growth of non-small cell lung cancer (NSCLC), one of the most common causes of cancer-related mortality. Although DEAD-box RNA helicases are known to play a role in cancer development, including lung cancer, the potential involvement of the novel family member DDX51 has not yet been investigated. In the current study we assessed the role of DDX51 in NSCLC using a siRNA-based approach. DDX51 siRNA-expressing cells exhibited a slower cell proliferation rate and underwent arrest in S-phase of the cell cycle compared with control cells. Microarray analyses revealed that DDX51siRNA expression resulted in the dysregulation of a number of cell signalling pathways. Moreover, injection of DDX51 siRNA into an animal model resulted in the formation of smaller tumours compared with the control group. We also assessed the expression of DDX51 in patients with NSCLC, and the data revealed that the expression was correlated with patient age but no other risk factors. Overall, our data suggest for the first time that DDX51 aids cell cancer proliferation by regulating multiple signalling pathways, and that this protein might be a therapeutic target for NSCLC.

| S-EPMC4873746 | biostudies-literature

Acquired dependence of acute myeloid leukemia on the DEAD-box RNA helicase DDX5.

Project description:Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS). This apoptotic response can be blocked either by BCL2 overexpression or treatment with the ROS scavenger N-acetyl-L-cysteine. Combining DDX5 knockdown with a BCL2 family inhibitor cooperates to induce cell death in AML cells. By inhibiting DDX5 expression in vivo, we show that DDX5 is dispensable for normal hematopoiesis and tissue homeostasis. These results validate DDX5 as a potential target for blocking AML.

| S-EPMC4100070 | biostudies-literature

DDX5 promotes proliferation and tumorigenesis of non-small-cell lung cancer cells by activating β-catenin signaling pathway.

Project description:The DEAD-box-protein DDX5 is an ATP-dependent RNA helicase that is frequently overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. DDX5 is reported to be involved in cancer progression by promoting cell proliferation and epithelial-mesenchymal transition. However, the clinical significance and biological role of DDX5 in non-small-cell lung cancer (NSCLC) remain largely unknown. In this study, we examined the expression of DDX5 in clinical NSCLC samples, investigated its role in regulating NSCLC cell proliferation and tumorigenesis, and explored the possible molecular mechanism. We found that DDX5 was significantly overexpressed in NSCLC tissues as compared with the matched normal adjacent tissues. In addition, overexpression of DDX5 was associated with advanced clinical stage, higher Ki67 index, and shorter overall survival in NSCLC patients. Upregulation of DDX5 promoted proliferation of NSCLC cells in vitro and growth of NSCLC xenografts in vivo, whereas downregulation of DDX5 showed the opposite effects. Furthermore, DDX5 directly interacted with β-catenin, promoted its nuclear translocation, and co-activated the expression of cyclin D1 and c-Myc. β-catenin silencing significantly abrogated DDX5-induced cyclin D1 and c-Myc expression and proliferation in NSCLC cells. Interestingly, DDX5 and cyclin D1 expression followed positive correlation in the same set of NSCLC samples. These findings indicated that DDX5 played an important role in the proliferation and tumorigenesis of NSCLC cells by activating the β-catenin signaling pathway. Therefore, DDX5 may serve as a novel prognostic marker and potential therapeutic target in the treatment of NSCLC.

| S-EPMC4638002 | biostudies-literature

Silencing of Long Non-Coding RNA FGD5-AS1 Inhibits the Progression of Non-Small Cell Lung Cancer by Regulating the miR-493-5p/DDX5 Axis.

Project description:BackgroundLong non-coding RNA FGD5 antisense RNA 1 (FGD5-AS1), identified to be a carcinogenic lncRNA, exhibits a regulatory role in some malignancies including non-small cell lung cancer (NSCLC). The aim of the present research is to decipher the function and underlying mechanism of FGD5-AS1 in progression of NSCLC.MethodsExpression of FGD5-AS1, miR-493-5p and DEAD-box protein 5 (DDX5) in NSCLC tissues and cells was quantified utilizing qRT-PCR. Cell proliferation was assessed by CCK-8 method. Scratch healing test and Transwell assay were used for assaying cell migration and invasion. Expressions of DDX5 and epithelial-mesenchymal transition (EMT)-related proteins were examined by Western blot. Additionally, targeting relationships between FGD5-AS1 and miR-493-5p, miR-493-5p and DDX5 were verified by dual-luciferase reporter gene assay.ResultsExpression of FGD5-AS1 in NSCLC tissues and cell lines was up-regulated. Expression of FGD5-AS1 was in association with enlarged tumor size and lymph node metastasis of the patients. Knockdown of FGD5-AS1 led to the inhibition of proliferation, migration, invasion and EMT of NSCLC cells. FGD5-AS1 directly targeted miR-493-5p, while DDX5 was the target of miR-493-5p in NSCLC cells. Additionally, FGD5-AS1 could positively regulate the expression of DDX5 via suppressing miR-493-5p.ConclusionFGD5-AS1 facilitates the proliferation, migration, invasion and EMT of NSCLC cells by sponging miR-493-5p and up-regulating DDX5.

| S-EPMC7876571 | biostudies-literature

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