SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.

Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.