Glucose starvation impairs DNA repair in tumour cells selectively by blocking histone acetylation

Ampferl, Rena; Rodemann, H. Peter; Mayer, Claus; Höfling, T. Tim A.; Dittmann, Klaus

doi:10.1016/j.radonc.2017.10.020

Cited by 21 publications

(14 citation statements)

References 22 publications

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“…[60] Amongst various changes there are effects on the DDR, [61] with longer term glucose withdrawal resulting in inhibition of DNA repair pathways that can give rise to accumulated levels of DNA damage. [42] Consistently we observed that glucose withdrawal increased genome damage in our cell line models with further analysis showing an implicit association with this phenotype and the presence of Vanguard. We also established that Vanguard cellular levels and function were proportional to glucose availability.…”

Section: Discussionsupporting

confidence: 88%

Vanguard is a Glucose Deprivation‐Responsive Long Non‐Coding RNA Essential for Chromatin Remodeling‐Reliant DNA Repair

et al. 2022

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Glucosemetabolism contributes to DNA damage response pathways by regulating chromatin remodeling, double-strand break (DSB) repair, and redox homeostasis, although the underlying mechanisms are not fully established. Here, a previously uncharacterized long non-coding RNA is revealed that is call Vanguard which acts to promote HMGB1-dependent DNA repair in association with changes in global chromatin accessibility. Vanguard expression is maintained in cancer cells by SP1-dependent transcription according to glucose availability and cellular adenosine triphosphate (ATP) levels. Vanguard promotes complex formation between HMGB1 and HDAC1, with the resulting deacetylation of HMGB1 serving to maintain its nuclear localization and DSB repair function. However, Vanguard downregulation under glucose limiting conditions promotes HMGB1 translocation from the nucleus, increasing DNA damage, and compromising cancer cell growth and viability. Moreover, Vanguard silencing increases the effectiveness of poly (ADP-ribose) polymerase inhibitors against breast cancer cells with wild-type breast cancer gene-1 status, suggesting Vanguard as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 88%

Vanguard is a Glucose Deprivation‐Responsive Long Non‐Coding RNA Essential for Chromatin Remodeling‐Reliant DNA Repair

et al. 2022

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“…Lack of glutamine led to DNA alkylation damage by inhibiting ALKBH activity and increased the sensitivity of cancer cells to alkylating agents ( Tran et al, 2017 ). Glucose starvation also enhanced radiosensitivity of tumor cells by reducing DNA double-strand break (DSB) repair ( Ampferl et al, 2018 ). Thus, the dysregulation of DNA repair pathways can contribute to the development of cancer by promoting genomic instability and mutation in mammal cells.…”

Section: Role Of Dna Repair Pathways In Cancer Biologymentioning

confidence: 99%

DNA Repair Pathways in Cancer Therapy and Resistance

et al. 2021

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DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.

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“…In addition, LDHA controls a most potent pathway of rapid ATP production in cancer cells and its blockage deprives cancer cells from a major energy pathway, which may shift cell metabolism from glycolysis to mitochondrial oxidative phosphorylation(OXPHOS) and generate more ROS [33]. Combination of oxamate with radiation becomes more e cient in suppressing ATP formation and reducing DNA repair ability [34,35]. Of particular interest, one recent study revealed that tumor metabolites, including 2-hydroxyglutarate, fumarate hydratase, and α-ketoglutarate, hindered DNA repair by disrupting local chromatin signaling [36], demonstrating the importance of metabolism in DNA repair activity.…”

Section: Discussionmentioning

confidence: 99%

Targeting Lactate Dehydrogenase A Improves Radiotherapy Efficacy in Non-Small Cell Lung Cancer: From Bedside to Bench

Yang

Chong

Dai

et al. 2021

Preprint

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BackgroundLDHA is overexpressed in many kinds of cancer, and associated with poor prognosis. In the current study, we evaluated the prognostic value of LDHA expression in non-small cell lung cancer (NSCLC), and tested whether LDHA inhibition might improve radiotherapy efficacy in NSCLC.MethodsLDHA mRNA expression was investigated in NSCLC patients, using online database and further verified by immunohistochemistry. The prognostic value of LDHA was evaluated using Kaplan-Meier plotter database. In vitro, two NSCLC cell lines were pretreated with oxamate, an inhibitor of LDHA, and colony formation method was performed to determine cellular radiosensitivity. Comet assay was used to detect DNA damage after irradiation. Flow cytometry was applied to test cell cycle progression and apoptosis, and autophagy was examined by monodansylcadaverin (MDC) staining.ResultsBoth mRNA and protein levels of LDHA expression were up-regulated in NSCLC tissues. High LDHA expression was a poor prognostic factor and associated with radioresistance in NSCLC patients. LDHA inhibition by oxamate remarkably increased radiosensitivity in both A549 and H1975 cancer cells, and enhanced ionizing radiation (IR)-induced apoptosis and autophagy, accompanied by cell cycle distribution alternations. Furthermore, LDHA inhibition induced reactive oxygen species (ROS) accumulation and cellular ATP depletion, which might increase DNA injury and hinder DNA repair activity.ConclusionsOur study suggests inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.

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Glucose starvation impairs DNA repair in tumour cells selectively by blocking histone acetylation

Cited by 21 publications

References 22 publications

Vanguard is a Glucose Deprivation‐Responsive Long Non‐Coding RNA Essential for Chromatin Remodeling‐Reliant DNA Repair

Vanguard is a Glucose Deprivation‐Responsive Long Non‐Coding RNA Essential for Chromatin Remodeling‐Reliant DNA Repair

DNA Repair Pathways in Cancer Therapy and Resistance

Targeting Lactate Dehydrogenase A Improves Radiotherapy Efficacy in Non-Small Cell Lung Cancer: From Bedside to Bench

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