Abstract 2759: Chemoproteomic profiling of the oncometabolite fumarate

Dysregulated metabolism is a feature of many diseases, including cancer. In addition to providing energy and building blocks to growing cells, altered metabolism can assist in tumor growth by producing “oncometabolites”. For example, in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) inactivating mutations in fumarate hydratase (FH) leads to accumulation of millimolar levels of an oncometabolite, fumarate. At such high concentrations, fumarate can spontaneously react with protein cysteine residues leading to a post-translational modification (PTM) called cysteine succination. This PTM can directly stimulate tumorigenic signaling, however, current methods to study this PTM are limited. Our lab has developed chemical proteomic methods to investigate proteome-wide targets of cysteine succination. Using these methods, we have identified hundreds of targets of fumarate in normal kidney cells as well as HLRCC cells. One interesting target identified that has implications in cancer progression is SMARCC1, a core subunit of a nucleosome remodeling complex known as the SWI/SNF complex. The SWI/SNF complex is a well-known tumor suppressor and mutation of this complex leads to cancer development. We have demonstrated that excess fumarate levels result in hyper-modification of SMARCC1 and decrease in SWI/SNF complex stability. This instability also results in an increase in EZH2 expression as well as activity, and an increase in H3K27Me3. Our current efforts are aimed at understanding how fumarate affects the function of this complex in vivo and exploring the potential of using EZH2 inhibitors in the treatment of HLRCC. Citation Format: Sarah E. Bergholtz, Chloe A. Briney, Rhushikesh A. Kulkarni, David Wei, Daniel W. Bak, Jonathan H. Shrimp, Eranthie Weerapana, W. Marston Linehan, Jordan L. Meier. Chemoproteomic profiling of the oncometabolite fumarate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2759.