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.
According to the World Health Organization (WHO), the incidence of melanoma is increasing faster than any other cancer. Currently, the median survival for metastatic melanoma is still in the realm of 12-14 months and there are few therapies that offer a significant improvement in overall survival. Special effort has been given t understanding the regulation of this cancer at the molecular level in order to identify new therapeutic targets. Among them, epigenetic changes, defined as modifications affecting gene expression without altering the DNA sequence, are capturing special attention due to their pivotal role in the pathogenesis of cancer and their potential modulation through pharmacological intervention. In this context, a family of drugs collectively known as histone deacetylase inhibitors (HDACi) regulates the packaging of DNA and interferes with other cellular functions, diminishing the proliferation of melanoma and enhancing recognition and clearance by the immune system. However, the non-specific action of these drugs encourages the development of more selective drugs which would target single master targets involved in the pathogenesis of cancer. In this application we propose to study HDAC6 as a potential target for modulating pathways related to the immunogenicity and proliferation of melanoma.
|Villagra, A; Sahakian, E; Seto, E (2016) Preparation and Biochemical Analysis of Classical Histone Deacetylases. Methods Enzymol 573:161-81|
|M, Lienlaf; P, Perez-Villarroel; T, Knox et al. (2016) Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Mol Oncol 10:735-750|
|Sahakian, Eva; Powers, John J; Chen, Jie et al. (2015) Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function. Mol Immunol 63:579-85|
|Woan, K V; Lienlaf, M; Perez-Villaroel, P et al. (2015) Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation. Mol Oncol 9:1447-1457|
|Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53|
|Cheng, Fengdong; Lienlaf, Maritza; Wang, Hong-Wei et al. (2014) A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol 193:2850-62|