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VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR

Oncogene volume 39, pages 4286–4298 (2020)Cite this article

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Abstract

It has been well established that the von Hippel-Lindau/hypoxia-inducible factor α (VHL-HIFα) axis and epidermal growth factor receptor (EGFR) signaling pathway play a critical role in the pathogenesis and progression of renal cell carcinoma (RCC). However, few studies have addressed the relationship between the two oncogenic drivers in RCC. SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase involved in gene transcription and oncogenesis, but its expression and function in RCC remain unclear. In the present study, we found that SMYD3 expression was significantly elevated in RCC tumors and correlated with advanced tumor stage, histological and nuclear grade, and shorter survival. Depletion of SMYD3 inhibited RCC cell proliferation, colony numbers, and xenograft tumor formation, while promoted apoptosis. Mechanistically, SMYD3 cooperates with SP1 to transcriptionally promote EGFR expression, amplifying its downstream signaling activity. TCGA data analyses revealed a significantly increased SMYD3 expression in primary RCC tumors carrying the loss-of-function VHL mutations. We further showed that HIF-2α can directly bind to the SMYD3 promoter and subsequently induced SMYD3 transcription and expression. Taken together, we identify the VHL/HIF-2α/SMYD3 signaling cascade-mediated EGFR hyperactivity through which SMYD3 promotes RCC progression. Our study suggests that SMYD3 is a potential therapeutic target and prognostic factor in RCC.

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Fig. 1: Enhanced SMYD3 expression in RCC tumors and its association with clinical outcomes.
Fig. 2: Effects of SMYD3 inhibition on tumorigenic and proliferation/survival potential of human RCC cells in vitro.
Fig. 3: SMYD3 knockdown impairs tumorigenic potential in RCC-derived cells.
Fig. 4: SMYD3 induces EGFR transcription and expression in human RCC cells.
Fig. 5: VHL inhibits SMYD3 expression in RCC cells and is negatively correlated with SMYD3 expression in RCC tumors.

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Acknowledgements

The study was funded by Peking University Medicine Fund of Fostering Young Scholars’ Scientific and Technological Innovation BMU2018PY003; the National Natural Science Foundation of China (Nos: 81711530048, 81572515, 81672522, and 81972381); Peking University Third Hospital Clinical Research Fund BYSY2018062 and BYSY2018012; the Fundamental Research funds for the Central Universities (No. 2020-JYB-XJSJJ-031); the Swedish Cancer Society, the Swedish Research Council, and Cancer Society in Stockholm.

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  1. These authors contributed equally: Cheng Liu, Li Liu

Authors and Affiliations

  1. Department of Urology, Peking University Third Hospital, Beijing, China

    Cheng Liu, Li-Yuan Ge, Run-Zhuo Ma, Min Qiu, Yi-Chang Hao, Yi Huang & Lu-Lin Ma

  2. School of Nursing, Beijing University of Chinese Medicine, Beijing, China

    Li Liu

  3. Key Lab for Cancer Prevention and Therapy, National Clinical Research Centre for Cancer, Department of Urology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Kun Wang

  4. Department of Urology, Shandong University Qilu Hospital, Jinan, China

    Xiao-Feng Li, Yi-Dong Fan, Lu-Chao Li & Zheng-Fang Liu

  5. Department of Urology, The People’s Hospital of Xinjiang Uyghur Autonomous Region, Xinjiang, China

    Li-Yuan Ge & Zhen-Feng Shi

  6. Department of Medicine, Division of Hematology, Bioclinicum and Centre for Molecular Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden

    Chuan-You Xia, Klas Strååt & Dawei Xu

  7. Karolinska Institute-Shandong University Collaborative Laboratory for Cancer and Stem Cell Research, Jinan, China

    Dawei Xu

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Liu, C., Liu, L., Wang, K. et al. VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR. Oncogene 39, 4286–4298 (2020). https://doi.org/10.1038/s41388-020-1291-7

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