Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells

(1) Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. (2) Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, includingSMO,PTCH1,GLI1,GLI2, andGLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of theSMOgene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putativeSMOpromoter elements were identified. Luciferase reporter assays mapped keySMOpromoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2 alpha transcription factors in the coreSMOpromoter region were confirmed. A hypermethylatedSMOpromoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing ofSMOexpression in certain cancer cells. (4) Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis ofSMOgene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation ofSMOexpression in cancer cells.