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MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription

Oncogene volume 34, pages 5570–5581 (2015)Cite this article

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Abstract

Malignant tumors are exemplified by excessive proliferation and aggressive migration/invasion contributing to increased mortality of cancer patients. Matrix metalloproteinase 9 (MMP9) expression is positively correlated with lung cancer malignancy. The mechanism underlying an elevated MMP9 expression is not clearly defined. We demonstrate here that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) was activated by hypoxia and transforming growth factor (TGF-β), two prominent pro-malignancy factors, in cultured lung cancer cells. MKL1 levels were also increased in more invasive types of lung cancer in humans. Depletion of MKL1 in lung cancer cells attenuated migration and invasion both in vitro and in vivo. Overexpression of MKL1 potentiated the induction of MMP9 transcription by hypoxia and TGF-β, whereas MKL1 silencing diminished MMP9 expression. Of interest, MKL1 knockdown eliminated histone H3K4 methylation surrounding the MMP9 promoter. Further analyses revealed that MKL1 recruited ASH2, a component of the H3K4 methyltransferase complex, to activate MMP9 transcription. Depletion of ASH2 ameliorated cancer cell migration and invasion in an MMP9-dependent manner. Together our data indicate that MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription.

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Acknowledgements

This work was supported, in part, by grants from the National Basic Science Project of China (2012CB517503), National Natural Science Foundation of China (31270805, 31200645, 81402550, 91439106), Natural Science Foundation of Jiangsu Province (BK2012043, BK20140906, BK21041498), Education Commission of Jiangsu Province (14KJA31001), the Program for New Century Excellent Talents in University of China (NCET-11-0991), Ministry of Education (212059, 20123234110008) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). YX is a fellow at the Collaborative Innovative Center for Cardiovascular Translational Medicine.

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  1. X Cheng and Y Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Cardiovascular Disease and Department of Pathophysiology, Nanjing Medical University, Nanjing, China

    X Cheng, Y Yang, Z Fan, L Yu, H Bai, B Zhou, X Wu, H Xu, M Fang, Q Chen & Y Xu

  2. Jiangsu Institute of Nuclear Medicine, Wuxi, China

    X Cheng

  3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    Y Yang

  4. Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China

    M Fang

  5. Department of Key Laboratory of Inflammation and Molecular Targets, Medical College, Nantong University, Nantong, China

    A Shen

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Cheng, X., Yang, Y., Fan, Z. et al. MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription. Oncogene 34, 5570–5581 (2015). https://doi.org/10.1038/onc.2015.14

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