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Molecular Cell Biology

Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression

Eva De Smedt, Ken Maes, Stefaan Verhulst, Hui Lui, Alboukadel Kassambara, Anke Maes, Nicolas Robert, Carlo Heirman, Andrew Cakana, Dirk Hose, Karine Breckpot, Leo A. van Grunsven, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jérôme Moreaux and Elke De Bruyne
Eva De Smedt
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Ken Maes
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Stefaan Verhulst
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
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Hui Lui
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
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Alboukadel Kassambara
Laboratory for Monitoring Innovative Therapies, Institute of Human Genetics, CNRS, Montpellier, France.
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Anke Maes
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Nicolas Robert
Laboratory for Monitoring Innovative Therapies, Institute of Human Genetics, CNRS, Montpellier, France.
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Carlo Heirman
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
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Andrew Cakana
Janssen Research and Development, High Wycombe, United Kingdom.
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Dirk Hose
Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
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Karine Breckpot
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
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Leo A. van Grunsven
Liver Cell Biology Laboratory, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
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Kim De Veirman
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Eline Menu
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Karin Vanderkerken
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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Jérôme Moreaux
Laboratory for Monitoring Innovative Therapies, Institute of Human Genetics, CNRS, Montpellier, France.
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Elke De Bruyne
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
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  • For correspondence: Elke.De.Bruyne@vub.be
DOI: 10.1158/0008-5472.CAN-17-1544 Published March 2018
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Abstract

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.

Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155–68. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received May 31, 2017.
  • Revision received November 15, 2017.
  • Accepted December 12, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Research: 78 (5)
March 2018
Volume 78, Issue 5
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Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression
Eva De Smedt, Ken Maes, Stefaan Verhulst, Hui Lui, Alboukadel Kassambara, Anke Maes, Nicolas Robert, Carlo Heirman, Andrew Cakana, Dirk Hose, Karine Breckpot, Leo A. van Grunsven, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jérôme Moreaux and Elke De Bruyne
Cancer Res March 1 2018 (78) (5) 1155-1168; DOI: 10.1158/0008-5472.CAN-17-1544

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Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression
Eva De Smedt, Ken Maes, Stefaan Verhulst, Hui Lui, Alboukadel Kassambara, Anke Maes, Nicolas Robert, Carlo Heirman, Andrew Cakana, Dirk Hose, Karine Breckpot, Leo A. van Grunsven, Kim De Veirman, Eline Menu, Karin Vanderkerken, Jérôme Moreaux and Elke De Bruyne
Cancer Res March 1 2018 (78) (5) 1155-1168; DOI: 10.1158/0008-5472.CAN-17-1544
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Cancer Research Online ISSN: 1538-7445
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