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, including , , , , and , were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative promoter elements were identified. Luciferase reporter assays mapped key promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core promoter region were confirmed. A hypermethylated promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of expression 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 of gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of expression in cancer cells.