Abstract A073: A link between the mitochondrial enzyme glutamic-oxaloacetic transaminase 2 (GOT2) and epigenetic dysregulation in pancreatic cancer

Abstract

Abstract At present, pancreatic cancer stands as the 3rd cause of cancer-related fatalities in the US. The most common type of pancreatic cancer develops from the exocrine pancreas known as ductal adenocarcinoma (PDAC). PDAC exhibits a highly aggressive nature and carries a bleak prognosis, with a 5-year survival rate averaging below 10%. Moreover, the majority of patients receive their diagnosis at advanced stages of the disease. Compounding the issue, the emergence of resistance to modern first-line chemotherapies contributes to the progression of PDAC and exacerbates its overall high mortality rate. The specific cause of PDAC remains unknown, although lifestyle factors such as alcohol and tobacco use, along with genetic abnormalities, have been linked to its increasing incidence over the past decade. Mutations in KRAS, TP53, SMAD4, and CDKN2A are recognized as genetic drivers contributing to the progression of PDAC. Recently, research has shifted its focus to investigating the role of epigenetic dysregulation in PDAC advancement. Significant evidence suggests that remodeling of the epigenome plays a crucial role in the development and progression of PDAC, but the exact mediators responsible for these alterations remain largely unknown. Recent studies have indicated that mitochondrial enzymes may influence epigenetic modifications, thus contributing to the progression of tumorigenesis. In our previous work, we reported that the mitochondrial protein GOT2 (glutamic-oxaloacetic transaminase) supports PDAC development by promoting an immunosuppressive phenotype within the tumor microenvironment. Ongoing epigenetic studies following ChIP- and ATAC-seq (chromatin immunoprecipitation and assay for transposase-accessible chromatin with sequencing, respectively) experiments in mammalian PDAC cell lines have revealed that loss of GOT2 leads to genome-wide changes in histone acetylation and chromatin accessibility. These changes in acetylation and chromatin architecture imply a reconfiguration of the epigenetic landscape and subsequent alterations in the PDAC transcriptome, suggesting a potential role for GOT2 in maintaining epigenetic profiles within the context of pancreatic cancer. Further exploration of the genomic regions where these histone modification changes occur has implicated cis-regulatory regions and the expression of their target genes, which may be crucial for PDAC progression. Collectively, these epigenetic studies hold the potential to identify novel therapeutic targets that could address the urgent need for more effective antineoplastic treatments against this aggressive form of pancreatic cancer. Citation Format: Luis Francisco Diaz, Mara H. Sherman, Jonathan R. Brody. A link between the mitochondrial enzyme glutamic-oxaloacetic transaminase 2 (GOT2) and epigenetic dysregulation in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A073.