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Article

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

by
Hong Lou
1,†,
Hongchuan Li
2,†,
Andrew R. Huehn
3,4,
Nadya I. Tarasova
3,
Bahara Saleh
3,
Stephen K. Anderson
2,3,* and
Michael Dean
5,*
1
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., National Laboratory for Cancer Research, Gaithersburg, MD 20892, USA
2
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
3
Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
4
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA
5
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD 20892, USA
*
Authors to whom correspondence should be addressed.
†
These authors equally contributed to this paper.
Cancers 2020, 12(8), 2219; https://doi.org/10.3390/cancers12082219
Submission received: 29 May 2020 / Revised: 17 July 2020 / Accepted: 28 July 2020 / Published: 8 August 2020
(This article belongs to the Special Issue Genetic Markers and Cancer Risk)
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Abstract

(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 SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO 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 SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells.
Keywords: hedgehog pathway; smoothened; promoter; methylation; transcription factors hedgehog pathway; smoothened; promoter; methylation; transcription factors

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MDPI and ACS Style

Lou, H.; Li, H.; Huehn, A.R.; Tarasova, N.I.; Saleh, B.; Anderson, S.K.; Dean, M. Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells. Cancers 2020, 12, 2219. https://doi.org/10.3390/cancers12082219

AMA Style

Lou H, Li H, Huehn AR, Tarasova NI, Saleh B, Anderson SK, Dean M. Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells. Cancers. 2020; 12(8):2219. https://doi.org/10.3390/cancers12082219

Chicago/Turabian Style

Lou, Hong, Hongchuan Li, Andrew R. Huehn, Nadya I. Tarasova, Bahara Saleh, Stephen K. Anderson, and Michael Dean. 2020. "Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells" Cancers 12, no. 8: 2219. https://doi.org/10.3390/cancers12082219

APA Style

Lou, H., Li, H., Huehn, A. R., Tarasova, N. I., Saleh, B., Anderson, S. K., & Dean, M. (2020). Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells. Cancers, 12(8), 2219. https://doi.org/10.3390/cancers12082219

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