Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1784732518853902336 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9221025 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wangyanwu aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT shenning aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT spurlingervase aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT kormsovannarith aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT huangsarah aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT andersonnicolem aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT huitingleahn aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT liuhudan aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting AT fenghui aketoglutaratemediateddnademethylationsustainstacutelymphoblasticleukemiaupontcacycletargeting |