Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors

• DOI: 10.1016/j.celrep.2023.113629
• Publication Date: 2023-12-30T23:20:30Z
• Authors: Dimitris Karagiannis; Warren Wu; Albert Li; Makiko Hayashi; Xiao Chen; Michaela Yip; Vaibhav Mangipudy; Xinjing Xu; Francisco J. Sánc...; Yadira M. Soto-Fe...; Jiangbin Ye; Thales Papagianna...; Chao Lu
• Keywords: Reprogramming; Histone deacetylase 5; Histone deacetylase inhibitor; HDAC10; HDAC11

The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether how metabolic reprogramming tumors generates vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that sensitizes LUAD cells to genetic chemical inhibition class I histone deacetylases (HDACs). This association observed across cultured cells, mouse models, patient-derived xenografts. Integrative epigenomic, transcriptomic, metabolomic analysis demonstrates HDAC causes widespread redistribution H4ac its reader protein, transcriptionally downregulates enzymes. results reduced flux into amino acid de novo nucleotide synthesis pathways are preferentially required for survival NRF2-active cells. Together, our findings suggest as potential biomarker effective repurposing inhibitors treat solid tumors.