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Myeloma

DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway

Leukemia volume 23, pages 383–390 (2009)Cite this article

Abstract

DLC1 (deleted in liver cancer 1), a tumor suppressor gene that encodes a RhoGTPase-activating protein, is recurrently downregulated or silenced in various solid tumors and hematological malignancies because of epigenetic modifications or genomic deletion. Here, we identified DLC1 promoter hypermethylation in 43 out of 44 multiple myeloma (MM) cell lines, which resulted in downregulation or silencing of DLC1 in 41 samples. High frequency of tumor-specific methylation and attenuation or silencing of DLC1 expression could serve as an independent diagnostic marker for MM. Combined treatment with demethylating and acetylating agents significantly elevated the expression of DLC1 and suppressed MM cell proliferation. Two cell lines exhibiting complete promoter methylation and the absence of DLC1 expression were transduced by an adenoviral vector containing DLC1 cDNA. In both cell lines, the reexpression of DLC1 inhibited myeloma cell invasion and migration, reduced RhoA activity and resulted in the reorganization of actin cytoskeleton. These results provide the first evidence for the antiproliferative effect of DLC1 in a hematological cancer and implicate RhoA pathway in suppression of MM migration and invasion. Given the myeloma cells sensitivity to the reactivation of DLC1 function, the potential for molecular targeted therapy of DLC1-mediated pathways as well as epigenetic therapies hold prospects.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Cancer Institute, NIH. We thank Dr Michael Kuehl (Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA) for providing DNA and RNA samples isolated from multiple myeloma cell lines, critical reading of the manuscript and most helpful suggestions. We also thank to Dr Sheng Chen for kindly providing plasma cells samples from healthy donors.

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Author notes

  1. V Ullmannova-Benson

    Present address: 2Present address: Laboratory of Innate Immunity, Academy of Sciences, Prague, Czech Republic.,

  2. M Guan

    Present address: 3Present Address: Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.,

Authors and Affiliations

  1. Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD, USA

    V Ullmannova-Benson, M Guan, X Zhou, V Tripathi, X-Y Yang, D B Zimonjic & N C Popescu

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Correspondence to N C Popescu.

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Ullmannova-Benson, V., Guan, M., Zhou, X. et al. DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway. Leukemia 23, 383–390 (2009). https://doi.org/10.1038/leu.2008.285

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