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

eLife

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[1] Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea;Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea;Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea;Department of Urology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea;Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea;

关键词: hedgehog signaling;    tumor stroma;    cancer subtype;    bladder cancer;    epigenetics;    BMP signaling;    Human;    Mouse;   

DOI  :  10.7554/eLife.43024

来源: publisher

【 摘 要 】

10.7554/eLife.43024.001In 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.

【 授权许可】

CC BY