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

Sungeun Kim, Yubin Kim, Jungho Kong, Eunjee Kim, Jae Hyeok Choi, Hyeong Dong Yuk, Hyesun Lee, Hwa Ryeon Kim, Kyoung Hwa Lee, Minyong Kang, Jae Seok Roe, Kyung Chul Moon, Sanguk Kim, Ja Hyeon Ku, Kunyoo Shin

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.

Original languageEnglish
Article numbere43024
Publication statusPublished - 2019 Apr

Bibliographical note

Funding Information:
We thank Phil Beachy for helpful discussion regarding this manuscript. This research was supported by grants from the National Research Foundation of Korea to K.S: NRF-2017R1A2B4006043, NRF-2017M3C7A1047875, NRF-2017R1A5A1015366 and the BK21 Plus Program.

Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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