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

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114430
• Main Authors: Olotu, Opeyemi, Koskenniemi, Anna-Riina, Ma, Lin, Paramonov, Valeriy, Laasanen, Sini, Louramo, Elina, Bourgery, Matthieu, Lehtiniemi, Tiina, Laasanen, Samuli, Rivero-Müller, Adolfo, Löyttyniemi, Eliisa, Sahlgren, Cecilia, Westermarck, Jukka, Ventelä, Sami, Visakorpi, Tapio, Poutanen, Matti, Vainio, Paula, Mäkelä, Juho-Antti, Kotaja, Noora
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-07-2024
• Subjects: cancer; cancer-germline antigens; DDX4; RNA regulation; RNP granules; tumor growth; RNA regulation; DDX4; CP: Cancer; RNP granules; CP: Molecular biology; tumor growth; cancer-germline antigens; cancer
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114430

Cancer cells undergo major epigenetic alterations and transcriptomic changes, including ectopic expression of tissue- and cell-type-specific genes. Here, we show that the germline-specific RNA helicase DDX4 forms germ-granule-like cytoplasmic ribonucleoprotein 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 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, the 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.
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•Germ-granule-resembling DDX4 granules appear in different somatic malignancies•Deletion of DDX4 in cancer cells compromises tumor growth•DDX4 deletion affects the expression of genes associated with cancer invasiveness•DDX4 expression is associated with poor survival of cancer patients
Olotu et al. reveal the presence of cytoplasmic granules containing the germline-specific RNA helicase DDX4 in various human cancers. Using cultured cancer cells and a mouse xenograft model, they show that DDX4 is involved in the transcriptome regulation in cancer cells, and it promotes cancerous properties and tumor growth.