There has been great progress in increasing the treatment options for patients who have the skin cancer melanoma in the past decade. However, the melanoma will most likely reappear and be resistant to more treatment options. There are specific types of melanoma cells which allow this to occur. We are currently targeting a protein called HDAC8 which plays a role in the cells which are resistant to therapy. This protein becomes active when the cell is under stress and regulates cell pathways which encourage cell survival. It does this by making the protein c-Jun, which is involved in the production of genes involved in cell growth and migration, more active. In this proposal we will determine how HDAC8 can stop drugs, stress and the immune system from killing cancer cells. We believe HDAC8 binds to DNA binding proteins which are involved in the production of RNA including c-Jun and CREB. When HDAC8 binds to CREB it stops it from being active. On the other hand when HDAC8 binds to c-Jun it activates it. We will look at the genes which are expressed either more or less by HDAC8. We will also test to see if the expression of HDAC8 can be lowered in mice and if lowering the expression of HDAC8 allows cells to be more receptive to established therapies and therapies which activate the immune system. We expect HDAC8 to become active and allow for a cell to become resistant to therapy by inactivating CREB and activating c-Jun. This allows for the increased production of RNA and proteins at sites in the DNA where c-Jun binds. We also expect that lowering the expression of HDAC8 will increase the response of patients to inhibitor therapy with melanoma and will increase the response of the immune system in fighting these cancers.