Abstract 5246: Histone deacetylase 6 (HDAC6) as a new modulator of the JAK/STAT pathway in melanoma.

Abstract

Abstract There is a crescent interest to understand the cellular and molecular processes involved in the progression of melanoma. Such knowledge is crucial for the development of more efficacious treatments and improved diagnostics. Acetylation and deacetylation of proteins plays a crucial role in the control of important cellular pathways, such as transcriptional control, proliferation, apoptosis, immunogenicity, etc. Specifically, histone deacetylases (HDACs) have garnered significant interest due to the availability of drugs that selectively inhibits HDAC. We recently investigated the effect of HDAC6 selective inhibitor(s) (HDAC6i) in human melanoma cell lines (WM164, WM983A and SKMEL21) with regards to proliferation and cell cycle profile. Pharmacological inhibition of HDAC6 resulted in a delayed proliferation and G1 cell cycle arrest in all melanoma cell lines analyzed. In addition to the pharmacological inhibition of HDAC6, we explored the effect of HDAC6 knock-down using specific shRNA (HDAC6KD). In agreement with the previous data from pharmacological inhibition of HDAC6, the proliferation of HDAC6KD melanoma cells was diminished when compared to wild-type and non-target shRNA control cells. Likewise, we observed a similar G1 arrest in the cell cycle that was attained with the use of HDAC6 specific inhibitors. Our data has also implicated HDAC6 in the regulation of the STAT1 and STAT3 pathways in melanoma cells. After cytokine IL-6 and IFN-γ stimulation of melanoma cells we found significant changes in the phosphorylation and acetylation status of STAT3 and STAT1 proteins in KDHDAC6 cells and/or treated with HDAC6i. Supporting this data, we observed important changes in the expression of STAT1 and STAT3 target genes, including essential genes involved in cell cycle control and immune regulation. Moreover, we observed a delay in tumor growth in C57BL/6 mice challenged in vivo with B16 cells lacking HDAC6 when compared to wild type B16 cells. These studies provide critical insights into the molecular pathways and/or partners that are involved in the regulatory role of HDAC6 in cell proliferation survival and cytokine signaling of human melanoma cells. Collectively, our data has identified HDAC6 as an attractive therapeutic target in melanoma due to its ability to delay tumor growth and target the JAK/STAT pathways, known to be altered in several melanoma malignancies. Citation Format: Maritza Lienlaf, Patricio Perez-Villarroel, Jorge Canales, Tessa Knox, Fengdong Cheng, Danay Marante, David Woods, Karrune Woan, HongWei Wang, Ed Seto, Jeffrey S. Weber, Eduardo M. Sotomayor, Alejandro Villagra. Histone deacetylase 6 (HDAC6) as a new modulator of the JAK/STAT pathway in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5246. doi:10.1158/1538-7445.AM2013-5246