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Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth

ABSTRACT: Cancer cells undergo major epigenetic alterations and transcriptome changes, including ectopic expression of many tissue- and cell type-specific genes. Here we show that the germline-specific RNA helicase DDX4 forms germ granule-like cytoplasmic ribonucleoprotein (RNP) granules in various human and mouse tumors, but not in cultured cancer cells. The DDX4-compexes in tumors contain RNA-binding proteins and splicing regulators, including many known germ granule components. The deletion of DDX4 in cancer cells induces transcriptome imbalance and affects the alternative splicing landscape of a large number of genes with reported functions in cancer growth and invasiveness, leading to their compromised capability to form xenograft tumors. Importantly, high expression of DDX4-positive granules is associated with poor survival in patients with squamous cell carcinoma of the head and neck, as well as with the histological grade of prostate cancer. Taken together, these results show that the formation of germ granule-resembling DDX4 granules have prognostic value, and they are involved in transcriptome control in cancer cells to promote malignant properties.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Lin Ma

LAB HEAD: Noora Kotaja

PROVIDER: PXD044856 | Pride | 2024-06-10

REPOSITORIES: Pride

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			Action	DRS
	210820_DDX4_IP1.msf	Msf
	210820_DDX4_IP1.mzML	Mzml
	210820_DDX4_IP1.raw	Raw
	210820_DDX4_IP2.msf	Msf
	210820_DDX4_IP2.mzML	Mzml

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Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth

Project description:Cancer cells undergo major epigenetic alterations and transcriptomic changes, including ectopic expression of many tissue- and cell type-specific genes. Here we show that the germline-specific RNA helicase DDX4 (DEAD-box helicase 4) forms germ granule-like cytoplasmic ribonucleoprotein (RNP) granules in various human tumors, but not in cultured cancer cells. These cancerous DDX4-complexes contain RNA-binding proteins and splicing regulators, including many known germ granule components. The deletion of DDX4 in cancer cells induces transcriptomic changes and affects the alternative splicing landscape of a large number of genes involved in cancer growth and invasiveness, leading to compromised capability of DDX4-null cancer cells to form xenograft tumors in immunocompromised mice. Importantly, occurrence of DDX4-granules is associated with poor survival in patients with head and neck squamous cell carcinoma, and higher histological grade of prostate cancer. Taken together, these results show that the germ granule-resembling cancerous DDX4-granules control gene expression and promote malignant and invasive properties of cancer cells.

2024-06-13 | GSE262574 | GEO

C. elegans germ granules regulate both germline and somatic RNAome [RNA-Seq]

Project description:Germ granules are membrane-less organelles essential for small RNA biogenesis and germline development. Among the conserved properties of germ granules is their association with the nuclear membrane. Recent studies demonstrated that LOTUS domain proteins, EGGD-1 and EGGD-2 (also known as MIP-1 and MIP-2 respectively), promote the formation of perinuclear germ granules in C. elegans. This finding presents a unique opportunity to evaluate the significance of perinuclear localization of germ granules. Here we show that loss of eggd-1 causes the coalescence of germ granules and formation of abnormal cytoplasmic aggregates. Impairment of perinuclear granules affects certain germline classes of small RNAs including Piwi-interacting RNAs. Transcriptome profiling reveals overexpression of spermatogenic and cuticle-related genes in eggd-1 hermaphrodites. We further demonstrate that disruption of germ granules activates HLH-30-mediated transcriptional program in somatic tissues. Collectively, our findings underscore the essential role of EGGD-1 in germ granule organization and reveal an unexpected germ granule-to-soma communication.

2023-07-20 | GSE228858 | GEO

C. elegans germ granules regulate both germline and somatic RNAome [miRNA-Seq]

2023-07-20 | GSE228857 | GEO

Transcriptome profiling of P-granule-depleted or P-granule mutant gonads versus control gonads over time

Project description:The germ cells of multicellular organisms protect their developmental potential through specialized mechanisms. A shared feature of germ cells from worms to humans is the presence of non-membrane-bound ribonucleoprotein organelles called germ granules. Depletion of germ granules in Caenorhabditis elegans (i.e., P granules) leads to sterility and in some germlines expression of the neuronal transgene unc-119::gfp and the muscle myosin MYO-3. Thus, P granules are hypothesized to maintain germ cell totipotency by preventing somatic development, although the mechanism by which P granules carry out this function is unknown. In this study, we performed transcriptome and single molecule RNA-FISH analyses of dissected P-granule-depleted gonads at different developmental stages. Our results demonstrate that P granules are necessary for adult germ cells to down-regulate spermatogenesis RNAs and to prevent the accumulation of numerous soma-specific RNAs. P-granule-depleted gonads that express the unc-119::gfp transgene also express many other genes involved in neuronal development and concomitantly lose expression of germ cell fate markers. Finally, we show that removal of either of two critical P-granule components, PGL-1 or GLH-1, is sufficient to cause germ cells to express UNC-119::GFP and MYO-3 and to display RNA accumulation defects similar to those observed after depletion of P granules. Our data identify P granules as critical modulators of the germline transcriptome and guardians of germ cell fate.

2016-12-22 | GSE92690 | GEO

CSR-1 and P granules suppress sperm-specific transcription in the C. elegans germline

Project description:P granules in C. elegans are required for fertility and function to maintain germ cell identity and pluripotency. Sterility in the absence of P granules is often accompanied by the mis-expression of soma-specific proteins and the initiation of somatic differentiation in germ cells. To investigate whether this is caused by the accumulation of somatic transcripts, we performed mRNA-seq on dissected germlines with and without P granules. Strikingly, we found that somatic transcripts do not increase in the young adult germline when P granules are impaired. Instead, we found that impairing P granules causes sperm-specific mRNAs to become highly overexpressed. This includes the accumulation of major sperm protein (MSP) transcripts in germ cells, a phenotype that is suppressed by feminization of the germline. A core component of P granules, the endo-siRNA-binding Argonaute protein CSR-1, has recently been ascribed with the ability to license transcripts for germline expression. However, impairing CSR-1 has very little effect on the accumulation of its mRNA targets. Instead, we found that CSR-1 functions with P granules to prevent MSP and sperm-specific mRNAs from being transcribed in the hermaphrodite germline. These findings suggest that P granules protect germline integrity through two different mechanisms, by 1) preventing the inappropriate expression of somatic proteins at the level of translational regulation, and by 2) functioning with CSR-1 to limit the domain of sperm-specific expression at the level of transcription. Four biological replicates of each condition (empty vector control, P granule RNAi, and CSR-1 RNAi germlines) were collected for total RNA.

2015-05-20 | E-GEOD-67954 | biostudies-arrayexpress

HeberleRazquinNavas2019 - The PI3K and MAPK/p38 pathways control stress granuleassembly in a hierarchical manner model 3

Project description:All cells and organisms exhibit stress-coping mechanisms toensure survival. Cytoplasmic protein-RNA assemblies termedstress granules are increasingly recognized to promote cellularsurvival under stress. Thus, they might represent tumor vul-nerabilities that are currently poorly explored. The translation-inhibitory eIF2αkinases are established as main drivers ofstress granule assembly. Using a systems approach, we identifythe translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regu-lator mammalian target of rapamycin complex 1 (mTORC1) topromote stress granule assembly. When highly active, PI3K is themain driver of stress granules; however, the impact of p38becomes apparent as PI3K activity declines. PI3K and p38 thusact in a hierarchical manner to drive mTORC1 activity and stressgranule assembly. Of note, this signaling hierarchy is also presentin human breast cancer tissue. Importantly, only the recognition ofthe PI3K-p38 hierarchy under stress enabled the discovery of p38’srole in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as theyhierarchically promote stress granule formation

2024-09-02 | BIOMD0000000907 | BioModels

HeberleRazquinNavas2019 - The PI3K and MAPK/p38 pathways control stress granuleassembly in a hierarchical manner model 2

Project description:All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

2024-09-26 | MODEL2001030002 | BioModels

The TDRD5/7-like protein, LOTR-1, functions within Z granules to balance epigenetic signals in the Caenorhabditis elegans germline

Project description:LOTUS and Tudor domain containing proteins have critical roles in the germline. Proteins that contain these domains, such as Tejas/Tapas in Drosophila, help localize Vasa to the germ granules and facilitate piRNA transposon mediated silencing. The homologous proteins in mammals, TDRD5 and TDRD7, are required during spermiogenesis. Until now, LOTUS + Tudor domain proteins in C. elegans have remained elusive. Here we describe LOTR-1 (D1081.7), which derives its name from its LOTUS and Tudor domains. Interestingly, LOTR-1 docks next to P granules to colocalize with the Z-granule component ZNFX-1. LOTR-1’s Z-granule association requires its Tudor domain, but both LOTUS and Tudor deletions affect brood size when coupled with a knockdown of the Vasa homolog glh-1. LOTR-1 IP-mass spectrometry confirmed a Tudor-dependent association with Z-granule proteins ZNFX-1 and WAGO-1, but also with germ-granule proteins DEPS-1, the piRNA Argonaute PRG-1, and other WAGO-class Argonautes. Like znfx-1, lotr-1 mutants redistribute the coverage of 22G-RNAs toward the 5’ end of mutator targets and impact transgenerational epigenetic inheritance. Unlike znfx-1, the 5’ shift in 22G-RNA coverage does not extend to CSR-1 targets. Combined, these results suggest that LOTR-1 facilitates interactions between PRG-1/WAGO-class Argonautes, ZNFX-1 and target 3’UTRs to balance 22G-RNA distribution across mutator targets.

2022-05-28 | PXD025186 | Pride

Spatiotemporal regulation of liquid-like condensates in epigenetic inheritance

Project description:Non-membrane bound organelles such as nucleoli, processing bodies, cajal bodies, and germ granules form via spontaneous self-assembly of specific proteins and RNAs. How these biomolecular condensates form and interact are poorly understood. Here we identify two proteins (ZNFX-1 and WAGO-4) that localize to C. elegans germ granules (P granules) in early germline blastomeres. Later in germline development, ZNFX-1/WAGO-4 separate from P granules to define an independent liquid-like condensate that we term the Z granule. In adult germ cells, Z granules assemble into ordered tri-droplet assemblages with P granules and Mutator foci that we term the PZM granule. Finally, we show that one biological function of ZNFX-1 and WAGO-4 is to interact with RNAs in the C. elegans germline to promote transgenerational epigenetic inheritance (TEI). We speculate that the temporal and spatial ordering of liquid droplet organelles may help cells organize and coordinate the complex RNA processing pathways underlying gene regulatory systems, such as RNA-directed TEI.

2018-03-21 | GSE112109 | GEO

Germ granules coordinate RNA-based epigenetic inheritance pathways

Project description:Germ granules are biomolecular condensates that promote germ cell totipotency in most, if not all, animals. In C. elegans, MEG-3 and MEG-4 are two intrinsically disordered proteins that are redundantly required for the phase separations that drive germ granule assembly in germline blastomeres. Here, we show that animals lacking MEG-3/4 exhibit defects in dsRNA-mediated gene silencing (RNAi) that are due, at least in part, to defects in systemic RNAi. Interestingly, these RNAi defects are transgenerationally disconnected from meg-3/4 genotype: RNAi defects do not arise until 5-9 generations after animals become mutant for meg-3/4, and RNAi defects persist for 9-11 generations after meg-3/4 genotype is restored to wild type. Similar non-Mendelian patterns of inheritance are associated with other mutations that disrupt germ granule formation, indicating that germ granule disruption is the likely cause of genotype/phenotype disconnects. Loss of germ granules is associated with the production of aberrant populations of endogenous siRNAs, which, remarkably, are propagated for ≅10 generations in wild-type descendants of animals that lacked germ granules. sid-1, which encodes a factor required for systemic RNAi in C. elegans, is inappropriately and heritably silenced by aberrantly expressed sid-1 endogenous siRNAs, suggesting that transgenerational silencing of sid-1 likely underlies the heritable defect in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that failure to assemble germ granules has consequences that persist across many generations.

2019-08-08 | GSE134683 | GEO

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