Histone deacetylases (HDACs), originally described as histone modifiers have more recently been demonstrated to modify a variety of other proteins involved in diverse cellular processes unrelated to the chromatin environment. This includes deacetylation of multiple non-histone targets, such as proteins involved in cell cycle/apoptosis and immune regulation. This expanded role raises the possibility that the effects of HDACs and HDACi may affect non-epigenetic regulatory pathways. In contrast to the well-documented effects of HDACi in the control of cell cycle and apoptosis, their role in immunobiology is still nt completely understood, and the reported immunological outcomes when using HDACi are heterogeneous. In this context, this application presents preliminary data showing that the pharmacological or genetic abrogation of a single HDAC, HDAC6, modifies the immunogenicity and proliferation of melanoma cells. Additionally, we have found that HDAC6 is overexpressed in most melanoma tumors, positioning this HDAC as an attractive target to pursue. Fortunately, there are multiple HDAC6-selective inhibitors available to mechanistically study the role of HDAC6 on these processes and provide a viable therapeutic avenue, which may minimize undesirable side effects that are characteristic of pan-HDACi such as SAHA. The significance of this proposal lies on several levels. First, HDACi specific for HDAC6 are currently available, making its specific inhibition a readily translatable option. Secondly, HDAC6 also interacts with proteins that play important roles in cancer progression (e.g. Hsp90) and cellular immunology (e.g. HDAC11). Additionally, in this application we present preliminary data that HDAC6 interacts with STAT3, which has been implicated in the pathogenesis of melanoma. Third, the inhibition of HDAC6 modulates the expression of MHC, PD-L1, melanoma specific tumor antigens, and other co-stimulatory molecules that modulate the immune response against melanoma. Lastly, HDAC6 is over-expressed in most primary melanoma samples. The above observations together with our recent findings, described in detail in this application, provide th rationale to mechanistically address the role of HDAC6 and its associated proteins in the pathogenesis of melanoma. Therefore, the central hypothesis to be tested in this application is whether the manipulation of HDAC6 and/or its molecular partners affects the proliferation and modulates immune-related pathways in melanoma cells.