Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer
- Pohang University of Science and Technology, Korea (South), Republic of
- Seoul National University Hospital, Korea (South), Republic of
- Yonsei University, Korea (South), Republic of
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea (South), Republic of
- 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.
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Comprehensive molecular characterization of urothelial bladder carcinomaThe TCGA Data, doi:10.1038/nature12965.
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Author details
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.
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.
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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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
