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

SIMPLE SUMMARY: A promising anti-cancer strategy is to target the tumor’s dependence on particular nutrients. However, resistance to single-agent treatment is common due to the adaptability of cancer cells. This research seeks to understand how T acute lymphoblastic leukemia (T-ALL) escapes disrupti...

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Autores principales: Wang, Yanwu, Shen, Ning, Spurlin, Gervase, Korm, Sovannarith, Huang, Sarah, Anderson, Nicole M., Huiting, Leah N., Liu, Hudan, Feng, Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221025/
https://www.ncbi.nlm.nih.gov/pubmed/35740646
http://dx.doi.org/10.3390/cancers14122983
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author Wang, Yanwu
Shen, Ning
Spurlin, Gervase
Korm, Sovannarith
Huang, Sarah
Anderson, Nicole M.
Huiting, Leah N.
Liu, Hudan
Feng, Hui
author_facet Wang, Yanwu
Shen, Ning
Spurlin, Gervase
Korm, Sovannarith
Huang, Sarah
Anderson, Nicole M.
Huiting, Leah N.
Liu, Hudan
Feng, Hui
author_sort Wang, Yanwu
collection PubMed
description SIMPLE SUMMARY: A promising anti-cancer strategy is to target the tumor’s dependence on particular nutrients. However, resistance to single-agent treatment is common due to the adaptability of cancer cells. This research seeks to understand how T acute lymphoblastic leukemia (T-ALL) escapes disruption of the tricarboxylic acid (TCA) cycle, a biochemical pathway critical for T-ALL survival. We show that leukemic cells modify their DNA to increase the activity of other pathways to compensate for diminished TCA cycle function. Our findings will help guide the rational selection of therapies to overcome drug resistance. 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.
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spelling pubmed-92210252022-06-24 α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting Wang, Yanwu Shen, Ning Spurlin, Gervase Korm, Sovannarith Huang, Sarah Anderson, Nicole M. Huiting, Leah N. Liu, Hudan Feng, Hui Cancers (Basel) Article SIMPLE SUMMARY: A promising anti-cancer strategy is to target the tumor’s dependence on particular nutrients. However, resistance to single-agent treatment is common due to the adaptability of cancer cells. This research seeks to understand how T acute lymphoblastic leukemia (T-ALL) escapes disruption of the tricarboxylic acid (TCA) cycle, a biochemical pathway critical for T-ALL survival. We show that leukemic cells modify their DNA to increase the activity of other pathways to compensate for diminished TCA cycle function. Our findings will help guide the rational selection of therapies to overcome drug resistance. 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. MDPI 2022-06-16 /pmc/articles/PMC9221025/ /pubmed/35740646 http://dx.doi.org/10.3390/cancers14122983 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Yanwu
Shen, Ning
Spurlin, Gervase
Korm, Sovannarith
Huang, Sarah
Anderson, Nicole M.
Huiting, Leah N.
Liu, Hudan
Feng, Hui
α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title_full α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title_fullStr α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title_full_unstemmed α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title_short α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting
title_sort α-ketoglutarate-mediated dna demethylation sustains t-acute lymphoblastic leukemia upon tca cycle targeting
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221025/
https://www.ncbi.nlm.nih.gov/pubmed/35740646
http://dx.doi.org/10.3390/cancers14122983
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