Projekt per år
Sammanfattning
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.
| Originalspråk | Engelska |
|---|---|
| Artikelnummer | 114430 |
| Antal sidor | 32 |
| Tidskrift | Cell Reports |
| Volym | 43 |
| Nummer | 7 |
| DOI | |
| Status | Publicerad - 23 juli 2024 |
| MoE-publikationstyp | A1 Tidskriftsartikel-refererad |
Finansiering
This work was supported by the Academy of Finland, the Turku doctoral program of molecular medicine, the Sigrid Jus\u00E9lius Foundation, the Novo Nordisk Foundation, the Jane and Aatos Erkko Foundation, and the Jalmari and Rauha Ahokas Foundation. We want to acknowledge the Turku Center for Disease Modeling, particularly Heli Niittym\u00E4ki, Heidi Liljenb\u00E4ck, and Katri Hovirinta, for the expert assistance in xenografting experiments; the Central Animal Facility of the University of Turku for the mouse facilities; and the Turku Bioscience Center for mass spectrometry and cell imaging facilities. We are grateful to Dr. Marcin Chrusciel and Dr. Nafis Rahman for generously giving us tumor samples for the initial testing of antibodies. We also thank Niina Smolander and Elina Tuomikoski for technical assistance in the experiments. O.O. and N.K. conceived and designed the study. O.O. A.-R.K. V.P. Sini Laasanen, E. Louramo, T.L. Samuli Laasanen, A.R.-M. P.V. and J.-A.M. designed and performed the laboratory experiments and analyzed the data. L.M. and M.B. analyzed the RNA-seq data. E. L\u00F6yttyniemi performed the statistical analyses of the human samples. C.S. J.W. S.V. T.V. and M.P. provided samples and other resources to the study. O.O. A.-R.K. J.-A.M. and N.K. interpreted the data and drafted the manuscript. All authors reviewed and edited the final version of the manuscript. The authors declare no competing interests. This work was supported by the Academy of Finland , the Turku doctoral program of molecular medicine, the Sigrid Jus\u00E9lius Foundation , the Novo Nordisk Foundation , the Jane and Aatos Erkko Foundation , and the Jalmari and Rauha Ahokas Foundation . We want to acknowledge the Turku Center for Disease Modeling, particularly Heli Niittym\u00E4ki, Heidi Liljenb\u00E4ck, and Katri Hovirinta, for the expert assistance in xenografting experiments; the Central Animal Facility of the University of Turku for the mouse facilities; and the Turku Bioscience Center for mass spectrometry and cell imaging facilities. We are grateful to Dr. Marcin Chrusciel and Dr. Nafis Rahman for generously giving us tumor samples for the initial testing of antibodies. We also thank Niina Smolander and Elina Tuomikoski for technical assistance in the experiments.
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