Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer

  1. SungEun Kim
  2. Yubin Kim
  3. JungHo Kong
  4. Eunjee Kim
  5. Jea Hyeok Choi
  6. Hyeong Dong Yuk
  7. HyeSun Lee
  8. Hwa-Ryeon Kim
  9. Kyoung-Hwa Lee
  10. Minyong Kang
  11. Jae-Seok Roe
  12. Kyung Chul Moon
  13. Sanguk Kim  Is a corresponding author
  14. Ja Hyeon Ku  Is a corresponding author
  15. Kunyoo Shin  Is a corresponding author
  1. Pohang University of Science and Technology, Korea (South), Republic of
  2. Seoul National University Hospital, Korea (South), Republic of
  3. Yonsei University, Korea (South), Republic of
  4. Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea (South), Republic of
  5. Seoul National University Hospital, Korea (South), Republic of

Abstract

In bladder, loss of mammalian Sonic Hedgehog (Shh) accompanies progression to invasive urothelial carcinoma, but the molecular mechanisms underlying this cancer-initiating event are poorly defined. Here, we show that loss of Shh results from hypermethylation of the CpG shore of the Shh gene, and that inhibition of DNA methylation increases Shh expression to halt the initiation of murine urothelial carcinoma at the early stage of progression. In full-fledged tumors, pharmacologic augmentation of Hedgehog (Hh) pathway activity impedes tumor growth, and this cancer-restraining effect of Hh signaling is mediated by the stromal response to Shh signals, which stimulates subtype conversion of basal to luminal-like urothelial carcinoma. Our findings thus provide a basis to develop subtype-specific strategies for the management of human bladder cancer.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 3, 4, 5, 6 and 7.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. SungEun Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  2. Yubin Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  3. JungHo Kong

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  4. Eunjee Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  5. Jea Hyeok Choi

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  6. Hyeong Dong Yuk

    Department of Urology, Seoul National University Hospital, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  7. HyeSun Lee

    Department of Urology, Seoul National University Hospital, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  8. Hwa-Ryeon Kim

    Department of Biochemistry, Yonsei University, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  9. Kyoung-Hwa Lee

    Department of Urology, Seoul National University Hospital, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  10. Minyong Kang

    Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  11. Jae-Seok Roe

    Department of Biochemistry, Yonsei University, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  12. Kyung Chul Moon

    Department of Pathology, Seoul National University Hospital, Seoul, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  13. Sanguk Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    For correspondence
    sukim@postech.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3449-3814
  14. Ja Hyeon Ku

    Department of Urology, Seoul National University Hospital, Seoul, Korea (South), Republic of
    For correspondence
    kuuro70@snu.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
  15. Kunyoo Shin

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea (South), Republic of
    For correspondence
    kunyoos@postech.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1519-9839

Funding

National Research Foundation of Korea (NRF-2017R1A2B4006043)

  • Kunyoo Shin

National Research Foundation of Korea (NRF-2017M3C7A1047875)

  • Kunyoo Shin

National Research Foundation of Korea (NRF-2017R1A5A1015366)

  • Kunyoo Shin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Martin McMahon, University of Utah Medical School, United States

Ethics

Animal experimentation: Mouse procedures were performed under isoflurane anesthesia with a standard vaporizer. All procedures were performed under a protocol approved by the Institutional Animal Care and Use Committee (IACUC) at POSTECH (POSTECH-2017-0094).

Human subjects: Frozen human bladder tissue samples were obtained from the tissue bank of Seoul National University Hospital. For fresh bladder tumor samples, 0.5-1 cm3 specimens of fresh bladder tissue were obtained from patients undergoing cystectomy or TURB under a protocol approved by the SNUH Institutional Review Board (IRB Number: 1607-135-777). Informed consent and consent to publish was obtained from the patients.

Version history

  1. Received: October 21, 2018
  2. Accepted: April 19, 2019
  3. Accepted Manuscript published: April 30, 2019 (version 1)
  4. Version of Record published: June 27, 2019 (version 2)

Copyright

© 2019, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. SungEun Kim
  2. Yubin Kim
  3. JungHo Kong
  4. Eunjee Kim
  5. Jea Hyeok Choi
  6. Hyeong Dong Yuk
  7. HyeSun Lee
  8. Hwa-Ryeon Kim
  9. Kyoung-Hwa Lee
  10. Minyong Kang
  11. Jae-Seok Roe
  12. Kyung Chul Moon
  13. Sanguk Kim
  14. Ja Hyeon Ku
  15. Kunyoo Shin
(2019)
Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer
eLife 8:e43024.
https://doi.org/10.7554/eLife.43024

Share this article

https://doi.org/10.7554/eLife.43024

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