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Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia

Oncogene volume 35, pages 4866–4880 (2016)Cite this article

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Abstract

It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.

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Acknowledgements

This work was supported by NIH grants (CA155477 and CA156700), George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial, Research Center of Excellence (DOH99-TD-B-111-004 to China Medical University, Taichung, Taiwan) and the National Science Foundation of China (31570775). We also gratefully acknowledged the help from Mr Jason Walrath of Department of Environmental Medicine of URMC for hypoxia experiments using In ViVo2 hypoxic workstation. We thank Karen Wolf for help preparing the manuscript.

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  1. W Zhai, Y Sun and M Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

    W Zhai & J Zheng

  2. Departments of Pathology, George Whipple Lab for Cancer Research, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA

    W Zhai, Y Sun, M Wang & C Chang

  3. Lab of Nuclear Receptors and Cancer Research, School of Medicine, Nantong University, Nantong, Jiangsu, China

    M Jiang

  4. Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA

    T A Gasiewicz

  5. Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan

    C Chang

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Zhai, W., Sun, Y., Jiang, M. et al. Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia. Oncogene 35, 4866–4880 (2016). https://doi.org/10.1038/onc.2016.19

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