Abstract A17: Glycosaminoglycans regulates histone acetylation status in multiple myeloma

Abstract

Histone acetylation modulates gene expression, cellular differentiation, and cell survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells and therefore HADC inhibitors are being actively studied as novel therapies in multiple myeloma. However, the mechanisms that regulate the acetylation levels of histones in myeloma remain unclear. We recently discovered that glycosaminoglycan (GAGs) chains of myeloma cells play an important role in regulating histone acetylation status. GAGs, such as chondroitin sulfate and heparan sulfate, which are expressed in the form serglycin and syndecan-1 proteoglycans, respectively, are highly expressed by myeloma cells and are present in the nucleus of these cells. Because exogenous GAGs are shown to both inhibit HAT activity and bind to the acetylation sites of histones, we hypothesized that reduction in GAGs would increase HAT activity and histone acetylation. We found that removal of GAGs from the nucleus of myeloma cells either by treatment with GAG degrading bacterial enzymes or by expressing the heparan sulfate degrading enzyme heparanase, significantly increased HAT activity and histone acetylation in myeloma cells. Further, the levels of acetylated histones are highly upregulated in tumors formed from cells expressing high levels of heparanase or cells that are silenced for syndecan-1 expression. BIACore assay showed that both chondroitin and heparan sulfates strongly bind to HAT enzyme p300. By dot blot assay we also demonstrate that both syndecan-1 and serglycin bind strongly to histones. Previous studies have shown that the negatively charged GAGs can bind to positively charged lysine residues (acetylation sites) on histone proteins. Overall our findings clearly demonstrate that GAGs decreases histone acetylation by both inhibiting HAT activity and by binding to acetylation sites of histones. This represents a novel mechanism for histone hypoacetylation, which is traditionally considered due to HDAC activity.

Citation Format: Anurag Purushothaman, Ralph D. Sanderson. Glycosaminoglycans regulates histone acetylation status in multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A17.