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The von Hippel–Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C

Oncogene volume 31, pages 776–786 (2012)Cite this article

Abstract

In clear-cell renal cell carcinoma (ccRCC), inactivation of the tumor suppressor von Hippel–Lindau (VHL) occurs in the majority of the tumors and is causal for the pathogenesis of ccRCC. Recently, a large-scale genomic sequencing study of ccRCC tumors revealed that enzymes that regulate histone H3 lysine 4 trimethylation (H3K4Me3), such as JARID1C/KDM5C/SMCX and MLL2, were mutated in ccRCC tumors, suggesting that H3K4Me3 might have an important role in regulating gene expression and tumorigenesis. In this study we report that in VHL-deficient ccRCC cells, the overall H3K4Me3 levels were significantly lower than that of VHL+/+ counterparts. Furthermore, this was hypoxia-inducible factor (HIF) dependent, as depletion of HIF subunits by small hairpin RNA in VHL-deficient ccRCC cells restored H3K4Me3 levels. In addition, we demonstrated that only loss of JARID1C, not JARID1A or JARID1B, abolished the difference of H3K4Me3 levels between VHL−/− and VHL+/+ cells, and JARID1C displayed HIF-dependent expression pattern. JARID1C in VHL−/− cells was responsible for the suppression of HIF-responsive genes insulin-like growth factor-binding protein 3 (IGFBP3), DNAJC12, COL6A1, growth and differentiation factor 15 (GDF15) and density-enhanced phosphatase 1. Consistent with these findings, the H3K4Me3 levels at the promoters of IGFBP3, DNAJC12, COL6A1 and GDF15 were lower in VHL−/− cells than in VHL+/+ cells, and the differences disappeared after JARID1C depletion. Although HIF2α is an oncogene in ccRCC, some of its targets might have tumor suppressive activity. Consistent with this, knockdown of JARID1C in 786-O VHL−/− ccRCC cells significantly enhanced tumor growth in a xenograft model, suggesting that JARID1C is tumor suppressive and its mutations are tumor promoting in ccRCC. Thus, VHL inactivation decreases H3K4Me3 levels through JARID1C, which alters gene expression and suppresses tumor growth.

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Acknowledgements

The 786-O and RCC4 cell lines were kind gifts from Dr William Kaelin Jr. This work was supported by American Cancer Society Pilot Award (to HY) and the seed fund from Cleveland Clinic to HY. QY is a Breast Cancer Alliance Young Investigator who was also supported by V scholar Award. We thank Dr Donal Luse for his critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    X Niu, T Zhang, L Liao, L Zhou & H Yang

  2. Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    D J Lindner & B Rini

  3. Department of Pathology, Cleveland Clinic, Cleveland, OH, USA

    M Zhou

  4. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    Q Yan

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Correspondence to H Yang.

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Niu, X., Zhang, T., Liao, L. et al. The von Hippel–Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene 31, 776–786 (2012). https://doi.org/10.1038/onc.2011.266

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