Sirtuin deacetylases: A new target for melanoma management

Abstract

y These authors contributed equally to this work.M elanoma 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.

Expression profile of SIRT2 in human melanoma and implications for sirtuin-based chemotherapy

“…[11][12][13] We observed that several chemical inhibitors of SIRT1 are capable of inhibiting melanoma cell growth and clonogenic survival in vitro. However, the inhibitors that were used in these studies, while specific for sirtuins, had the unintended effect of targeting both SIRT1 and SIRT2.…”

Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?

“…Wilking et al (17), studied the action of SIRT-1 inhibitors and found that the inhibition of SRT1 decreases the phosphorylation of PIP2 in PIP3 by inhibiting PI3K so the cell migration is limited (13). SIRT-1 inhibitors can increase the levels of p53 and p21, two proteins which are important for the cell-cycle arrest to inhibit the proliferation of tumor cells (17). The role of SIRT-1 in melanoma is beginning to be unraveled only recently and SIRT-1 inhibition seem to affect p53 protein levels in wild-type p53 melanoma cells, while several other pathways may be affected by SIRT-1 inhibition, including a possible role in cell-cycle regulation.…”

“…SIRT-1 is a member of the class III HDAC known as the Sirtuins, which depend on nicotinamide adenine dinucleotide (NADC) as a substrate. Wilking et al (17), studied the action of SIRT-1 inhibitors and found that the inhibition of SRT1 decreases the phosphorylation of PIP2 in PIP3 by inhibiting PI3K so the cell migration is limited (13). SIRT-1 inhibitors can increase the levels of p53 and p21, two proteins which are important for the cell-cycle arrest to inhibit the proliferation of tumor cells (17).…”

Sirtuin1 Expression and Correlation with Histopathological Features in Retinoblastoma

“…Moreover, Sirt1 inhibitors (Sirtinol, Tenovin-1 and Ex-527) have shown preclinical activity in breast cancer and melanoma by targeting the p53 and PI3K pathway [9,10]. This class of drugs may provide an effective novel therapy in retinoblastoma if Sirt1 is involved in the pathogenesis.…”

“…Retinoblastoma protein functions to regulate the G1/S transition of the cell cycle through its interaction with the E2F family of transcription factors [6]. The activity of retinoblastoma protein is regulated predominantly by phosphorylation and dephosphorylation.…”