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

Opeyemi Olotu; Anna-Riina  Koskenniemi; Lin  Ma; Valeriy Paramonov; Sini Laasanen; Elina Louramo; Matthieu  Bourgery; Tiina Lehtiniemi; Samuli Laasanen; Adolfo Rivero-Müller; Eliisa  Löyttyniemi; Cecilia Sahlgren; Jukka Westermarck; Sami Ventelä; Tapio Visakorpi; Matti Poutanen; Paula Vainio; Juho-Antti Mäkelä; Noora Kotaja

doi:10.1016/j.celrep.2024.114430

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

Opeyemi Olotu
, Anna-Riina Koskenniemi
, Lin Ma
, Valeriy Paramonov
, Sini Laasanen
, Elina Louramo
, Matthieu Bourgery
, Tiina Lehtiniemi
, Samuli Laasanen
, Adolfo Rivero-Müller
, Eliisa Löyttyniemi
, Cecilia Sahlgren
, Jukka Westermarck
, Sami Ventelä
, Tapio Visakorpi
, Matti Poutanen
, Paula Vainio
, Juho-Antti Mäkelä
, Noora Kotaja

Research output: Contribution to journal › Article › Scientific › peer-review

5 Citations (Scopus)

60 Downloads (Pure)

Abstract

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.

Original language	English
Article number	114430
Number of pages	32
Journal	Cell Reports
Volume	43
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2024.114430
Publication status	Published - 23 Jul 2024
MoE publication type	A1 Journal article-refereed

Funding

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.

Keywords

Cancer
Molecular biology
DDX4
RNA regulation
RNP granules
Cancer-germline antigens
Tumor growth

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10.1016/j.celrep.2024.114430Licence: CC BY

1-s2.0-S2211124724007599-mainFinal published version, 7.06 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2024080964263

1 Finished
1 Active

Replication stress-induced Notch1 phosphorylation mediates sustained cancer cell proliferation during DNA damage
Sahlgren, C. (Principal Investigator)
Sigrid Jusélius Foundation
01/05/23 → 30/04/26
Project: Foundation
Notch counteracts replication stress to prevent cancer cell senescence
Sahlgren, C. (Principal Investigator)
Cancer Foundation Finland, Sigrid Jusélius Foundation
01/05/20 → 31/12/23
Project: Foundation

Cite this

Olotu, O., Koskenniemi, A.-R., Ma, L., Paramonov, V., Laasanen, S., Louramo, E., Bourgery, M., Lehtiniemi, T., Laasanen, S., Rivero-Müller, A., Löyttyniemi, E., Sahlgren, C., Westermarck, J., Ventelä, S., Visakorpi, T., Poutanen, M., Vainio, P., Mäkelä, J.-A., & Kotaja, N. (2024). Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth. Cell Reports, 43(7), Article 114430. https://doi.org/10.1016/j.celrep.2024.114430

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title = "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 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.",

keywords = "Cancer, Molecular biology, DDX4, RNA regulation, RNP granules, Cancer-germline antigens, Tumor growth",

author = "Opeyemi Olotu and Anna-Riina Koskenniemi and Lin Ma and Valeriy Paramonov and Sini Laasanen and Elina Louramo and Matthieu Bourgery and Tiina Lehtiniemi and Samuli Laasanen and Adolfo Rivero-M{\"u}ller and Eliisa L{\"o}yttyniemi and Cecilia Sahlgren and Jukka Westermarck and Sami Ventel{\"a} and Tapio Visakorpi and Matti Poutanen and Paula Vainio and Juho-Antti M{\"a}kel{\"a} and Noora Kotaja",

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doi = "10.1016/j.celrep.2024.114430",

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Olotu, O, Koskenniemi, A-R, Ma, L, Paramonov, V, Laasanen, S, Louramo, E, Bourgery, M, Lehtiniemi, T, Laasanen, S, Rivero-Müller, A, Löyttyniemi, E, Sahlgren, C, Westermarck, J, Ventelä, S, Visakorpi, T, Poutanen, M, Vainio, P, Mäkelä, J-A & Kotaja, N 2024, 'Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth', Cell Reports, vol. 43, no. 7, 114430. https://doi.org/10.1016/j.celrep.2024.114430

TY - JOUR

T1 - Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth

AU - Olotu, Opeyemi

AU - Koskenniemi, Anna-Riina

AU - Ma, Lin

AU - Paramonov, Valeriy

AU - Laasanen, Sini

AU - Louramo, Elina

AU - Bourgery, Matthieu

AU - Lehtiniemi, Tiina

AU - Laasanen, Samuli

AU - Rivero-Müller, Adolfo

AU - Löyttyniemi, Eliisa

AU - Sahlgren, Cecilia

AU - Westermarck, Jukka

AU - Ventelä, Sami

AU - Visakorpi, Tapio

AU - Poutanen, Matti

AU - Vainio, Paula

AU - Mäkelä, Juho-Antti

AU - Kotaja, Noora

PY - 2024/7/23

Y1 - 2024/7/23

N2 - 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.

AB - 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.

KW - Cancer

KW - Molecular biology

KW - DDX4

KW - RNA regulation

KW - RNP granules

KW - Cancer-germline antigens

KW - Tumor growth

U2 - 10.1016/j.celrep.2024.114430

DO - 10.1016/j.celrep.2024.114430

M3 - Article

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 114430

ER -

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

Abstract

Funding

Keywords

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Projects

Replication stress-induced Notch1 phosphorylation mediates sustained cancer cell proliferation during DNA damage

Notch counteracts replication stress to prevent cancer cell senescence

Cite this