Uveal melanoma (UM) is the most common intraocular malignancy in adults.,Despite improvements in surgical, radiation and chemotherapy treatments, the overall survival of UM and prognosis remain poor.,In the present study, we hypothesized that Sirtuin 1 and 2 (SIRT1/2), class III histone deacetylases (HDACs), were critical in controlling the destiny of bulk tumor cells and cancer stem cells (CSCs) of UM.,We testified this hypothesis in four lines of UM cells (92.1, Mel 270, Omm 1 and Omm 2.3).,Our results showed that inhibition of SIRT1/2 by Tenovin-6 induced apoptosis in UM cells by activating the expression of tumor suppressor genes such as p53 and elevating reactive oxygen species (ROS).,Tenovin-6 inhibited the growth of UM cells.,Tenovin-6 and vinblastine was synergistic in inducing apoptosis of UM cell line 92.1 and Mel 270.,Furthermore, Tenovin-6 eliminated cancer stem cells in 92.1 and Mel 270 cells.,In conclusion, our findings suggest that Tenovin-6 may be a promising agent to kill UM bulk tumor cells and CSCs.
The dynamics of tumor cell populations is hotly debated: do populations derive hierarchically from a subpopulation of cancer stem cells (CSCs), or are stochastic transitions that mutate differentiated cancer cells to CSCs important?,Here we argue that regulation must also be important.,We sort human melanoma cells using three distinct cancer stem cell (CSC) markers - CXCR6, CD271 and ABCG2 - and observe that the fraction of non-CSC-marked cells first overshoots to a higher level and then returns to the level of unsorted cells.,This clearly indicates that the CSC population is homeostatically regulated.,Combining experimental measurements with theoretical modeling and numerical simulations, we show that the population dynamics of cancer cells is associated with a complex miRNA network regulating the Wnt and PI3K pathways.,Hence phenotypic switching is not stochastic, but is tightly regulated by the balance between positive and negative cells in the population.,Reducing the fraction of CSCs below a threshold triggers massive phenotypic switching, suggesting that a therapeutic strategy based on CSC eradication is unlikely to succeed.