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Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B

Oncogene volume 35, pages 6281–6292 (2016)Cite this article

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Abstract

We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial–mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.

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Acknowledgements

This work was supported by grants from the Nature Science Foundation of China (no. 81225018 and no.81472385), the Fundamental Research Funds for the Central Universities (Sun Yat-Sen University Young Teachers Plan) (no. 14ykpy39), Natural Science Foundation of Guangdong Province (no. 2015A030313009), China and Science and Technology Foundation of the Guangdong Province, China (grant no. 2013B021800173).

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Author notes

  1. X-D Li, J-X Zhang, L-J Jiang and F-W Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    X-D Li, J-X Zhang, L-J Jiang, F-W Wang, L-L Liu, Y-J Liao, X-H Jin, W-H Chen, X Chen, S-J Guo, F-J Zhou, Y-X Zeng, X-Y Guan, Z-W Liu & D Xie

  2. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China

    X-D Li, L-J Jiang, X Chen, S-J Guo, F-J Zhou & Z-W Liu

  3. Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    J-X Zhang

  4. Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China

    X-Y Guan

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Li, XD., Zhang, JX., Jiang, LJ. et al. Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B. Oncogene 35, 6281–6292 (2016). https://doi.org/10.1038/onc.2016.165

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