Abstract 5812: Histone deacetylase 10 supports tumor growth under polyamine-limiting conditions

Abstract

Abstract Cytosolic histone deacetylase 10 (HDAC10) is specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N8-AcSpd is unknown. We hypothesized that HDAC10, by converting N8-AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting, anticancer therapies. Inhibitors of polyamine biosynthesis, such as difluoromethylornithine (DFMO), inhibit tumor growth but with compensatory uptake of extracellular polyamines that have limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. The current study uses CRISPR/Cas9-mediated HDAC10-knockout cell lines and recently developed, selective HDAC10 inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. Inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by the provision of physiological concentrations of exogenous N8-AcSpd, which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have particular value in improving the response to polyamine-blocking therapies. Citation Format: Tracy Murray Stewart, Raphael R. Steimbach, Jackson R. Foley, Aubry K. Miller, Robert A. Casero. Histone deacetylase 10 supports tumor growth under polyamine-limiting conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5812.