Abstract A115: HDAC1 inhibition unleashes adaptive metabolism in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited therapeutic options and has a plethora of metabolic alterations that promote tumor survival and growth. Histone deacetylase 1 (HDAC1) is upregulated in PDAC and histone deacetylates are therapeutic targets in cancer, but the functional impact of HDAC1 on metabolism or the metabolic effect of inhibiting its expression is largely unexplored in PDAC. Here we deleted HDAC1 in a panel of PDAC cell lines followed by phenotypic, transcriptomic, proteomic and metabolomic assays. We found that although HDAC1 deletion mostly led to impaired proliferation and clonogenic growth, the opposite outcome was observed in a representative basal-like cell line. In addition, upregulated glycolytic signatures, nucleotide-, amino acid- and redox metabolism emerged as consistent metabolic alterations underlying adaptation to HDAC1 inhibition. High throughput drug screen revealed that HDAC1 inhibition strongly synergized with inhibitors of proteasome, nucleotide pathway and redox metabolism to suppress the viability of PDAC cells. Our study has uncovered unappreciated metabolic adaptations induced upon HDAC1 deletion, exposing opportunities for combinatorial therapeutic interventions in pancreatic cancer.