α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting

Abstract

Despite the development of metabolism-based therapy for a variety of malignancies, resistance to single-agent treatment is common due to the metabolic plasticity of cancer cells. Improved understanding of how malignant cells rewire metabolic pathways can guide the rational selection of combination therapy to circumvent drug resistance. Here, we show that human T-ALL cells shift their metabolism from oxidative decarboxylation to reductive carboxylation when the TCA cycle is disrupted. The α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle regulates oxidative decarboxylation by converting α-ketoglutarate (α-KG) to succinyl-CoA, while isocitrate dehydrogenase (IDH) 1 and 2 govern reductive carboxylation. Metabolomics flux analysis of T-ALL reveals enhanced reductive carboxylation upon genetic depletion of the E2 subunit of KGDHC, dihydrolipoamide-succinyl transferase (DLST), mimicking pharmacological inhibition of the complex. Mechanistically, KGDHC dysfunction causes increased demethylation of nuclear DNA by α-KG-dependent dioxygenases (e.g., TET demethylases), leading to increased production of both IDH1 and 2. Consequently, dual pharmacologic inhibition of the TCA cycle and TET demethylases demonstrates additive efficacy in reducing the tumor burden in zebrafish xenografts. These findings provide mechanistic insights into how T-ALL develops resistance to drugs targeting the TCA cycle and therapeutic strategies to overcome this resistance.

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease

“…This resulted in sPD hNPCs in an efflux of carbon out of the citric acid cycle at the level of α-ketoglutarate, diminishing the production of reducing equivalents. This is in line with metabolomic flux analysis that revealed enhanced reductive carboxylation upon genetic deletion of OGDHC subunits 64 . Thus overall, the alterations in OGDHC activity seemed to introduce an sPD-specific state of hypometabolism marked by reduced glucose and glutamine metabolization, a reduced mitochondrial ATP production rate, as well as a reduced abundance of most quantified metabolites.…”

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

“…Strikingly, the combination treatment of enzalutamide and the TET2 inhibitor, Bobcat339 [56][57][58][59][60][61][62][63] , significantly impaired the growth of enzalutamide-resistant ZNF397-KO cells, as demonstrated in an in vitro cell viability assay (Fig. 6F).…”

Prognostic Significance of Cuproptosis-Related Gene Signatures in Breast Cancer Based on Transcriptomic Data Analysis

“…Consistent with other studies [ 35 ], our analysis indicated that PDHA1 is an independent prognostic factor for OS and has a positive correlation with histological type and tumor size. Finally, DLST is closely involved in cell metabolism, contributing to the transduction of α-ketoglutarate into succinyl-CoA10 in the TCA cycle in an irreversible manner [ 36 ]. In several cancer types, DLST is found to be negatively correlated with clinical outcomes [ 37 ].…”