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Cytoplasmic translocation of MTA1 coregulator promotes de-repression of SGK1 transcription in hypoxic cancer cells

Oncogene volume 36, pages 5263–5273 (2017)Cite this article

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Abstract

Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown. Here we have discovered that MTA1 is a novel corepressor of serum and glucocorticoid-inducible kinase 1 (SGK1). Surprisingly, this regulatory corepressive function of MTA1 is lost under hypoxia, allowing upregulation of SGK1 expression and engaging the MTA1–SGK1 axis for the benefit of the cell survival. The underlying mechanism of the noticed stimulation of SGK1 expression by hypoxia includes de-repression of SGK1 transcription because of hypoxia-triggered nucleus-to-cytoplasmic translocation of MTA1. In addition, the newly recognized cytoplasmic translocation of MTA1 was dependent on the chaperoning function of heat shock protein 90 (HSP90) and co-accompanied by the formation of MTA1, HSP90 and HIF1α complex under hypoxic condition but not under normoxic condition. Hypoxia-triggered redistribution of MTA1, SGK1 upregulation and cell survival functions were compromised by a pharmacological SGK1 inhibitor. In summary, for the first time, we report MTA1 regulation of SGK1 expression, hypoxia-dependent MTA1 translocation to the cytoplasm and de-repression of SGK1 transcription. These findings illustrate how cancer cells utilize a chromatin remodeling factor to engage a core survival pathway to support its cancerous phenotypes, and reveal new facets of MTA1–SGK1 axis by a physiologic signal in cancer progression.

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Acknowledgements

We thank Christie P Thomas, University of Iowa for the promoter construct pGL3bas_hsgkF4R4, Nirmalya Sen from Kumar’s laboratory for identifying SGK1 as a MTA1 target from an in-house, microarray data set generated using NIH grant CA098823. Assistance from Vipin Mohan Dan for MTT analyses, Indu Ramachandran (Core facility for FACS), Confocal Microscopy facility, as well as Prakash R and Ishaque P (Central Cell Line Repository) for hypoxia standardization. This work was supported by Department of Biotechnology, Government of India and Hezlin Marzook is supported by a Senior Research Fellowship from the Council of Science and Industrial Research (09/716(0142)/2010-EMR-1).

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  1. Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India

    H Marzook, S Deivendran, B George, G Reshmi, T R Santhoshkumar, R Kumar & M R Pillai

  2. Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA

    R Kumar

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Marzook, H., Deivendran, S., George, B. et al. Cytoplasmic translocation of MTA1 coregulator promotes de-repression of SGK1 transcription in hypoxic cancer cells. Oncogene 36, 5263–5273 (2017). https://doi.org/10.1038/onc.2017.19

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