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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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262574 | GEO | 2024/06/13

REPOSITORIES: GEO

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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 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.

2024-06-10 | PXD044856 | Pride

Combinatorial tagging generates a multi-purpose knock-in mouse model revealing phase separation-dependent germ granules in RNA homeostasis and germline development

Project description:A large resource of epitope-tagged or Cre/CreERT2-expressing mouse models are available for study of germ granules or germline development. The germ granules are proteinaceous, membraneless organelles implicated in germ cell differentiation and maturation; however, their protein and RNA transcript constituents, and their mechanistic insight remain not fully understood. Herein, we generated a versatile germline mouse model through combinatorial tagging of DDX4 for simultaneous expression of three cistronic coding products (C-terminal tagged DDX4 - DDX45HA, EGFP, and CreERT2) under the driving control of endogenous Ddx4 promoter. By leveraging the high-affinity HA tag, we optimized an efficient workflow for purification of germ granules (Chromatoid body, CB) from spermatids, and characterized the landscape of protein constituents and RNA transcripts in CB. Moreover, we explored and ascertained that DDX4-mediated, phase-separation dependent CB integrity is functionally important for recruiting distinctive long RNA transcripts and biogenesis of pachytene- and TE-derived piRNAs. Together, our study generated a versatile germline mouse model with a multiplicity of applications for germline study, and provided mechanistic insight into germline development as dictated by germ granules.

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