ABSTRACT
This Commentary highlights the article by Di Sante et al, which presents data supporting the status of SIRT1 as a tumor suppressor in prostate cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , Mitochondria/metabolism , Mitophagy , Prostatic Intraepithelial Neoplasia/metabolism , Sirtuin 1/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Humans , MaleABSTRACT
Melanoma continues to cause more deaths than any other skin cancer, necessitating the development of new avenues of treatment. One promising new opportunity comes in the form of mechanism-based therapeutic targets. We recently reported the overexpression and delocalization of the class III histone deacetylase SIRT1 in melanoma, and demonstrated that its small molecule inhibition via Tenovin-1 decreased cell growth and viability of melanoma cells, possibly by a p53 mediated induction of p21. Here, we support our data using additional SIRT inhibitors, viz. Sirtinol and Ex-527, which suggests possible benefits of concomitantly inhibiting more than one Sirtuin for an effective cancer management strategy. This "Extra View" paper also includes a discussion of our results in the context of similar recent and concurrent studies. Furthermore, we expand upon our findings in an analysis of new research that may link the cellular localization and growth effects of SIRT1 with the PI3K signaling pathway.
Subject(s)
Benzamides/therapeutic use , Carbazoles/therapeutic use , Group III Histone Deacetylases/antagonists & inhibitors , Melanoma/drug therapy , Molecular Targeted Therapy , Naphthols/therapeutic use , Apoptosis/drug effects , Benzamides/pharmacology , Carbazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Clone Cells , Humans , Melanoma/pathology , Models, Biological , Naphthols/pharmacology , Signal Transduction/drug effectsABSTRACT
Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to determine the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clinical human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, respectively. In addition, treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small molecule SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further experiments showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small molecule inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment.
Subject(s)
Acetanilides/pharmacology , Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Melanoma/drug therapy , Melanoma/metabolism , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/metabolism , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , Thiourea/analogs & derivatives , Tumor Suppressor Protein p53/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Humans , Melanocytes/drug effects , Melanocytes/metabolism , Melanoma/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Regulatory Elements, Transcriptional/drug effects , Sirtuin 1/genetics , Skin Neoplasms/pathology , Thiourea/pharmacology , Tumor Stem Cell Assay , Up-Regulation/drug effectsABSTRACT
Biologically, light including ultraviolet (UV) radiation is vital for life. However, UV exposure does not come without risk, as it is a major factor in the development of skin cancer. Natural protections against UV damage may have been affected by lifestyle changes over the past century, including changes in our sun exposure due to working environments, and the use of sunscreens. In addition, extended "day time" through the use of artificial light may contribute to the disruption of our circadian rhythms; the daily cycles of changes in critical bio-factors including gene expression. Circadian disruption has been implicated in many health conditions, including cardiovascular, metabolic and psychiatric diseases, as well as many cancers. Interestingly, the pineal hormone melatonin plays a role in both circadian regulation as well as protection from UV skin damage, and is therefore an important factor to consider when studying the impact of UV light. This review discusses the beneficial and deleterious effects of solar exposure, including UV skin damage, Vitamin D production, circadian rhythm disruption and the impact of melatonin. Understanding these benefits and risks is critical for the development of protective strategies against solar radiation.
