How DNA methylation affects the Warburg effect

Zhu, Xiaomei; Xuan, Zefeng; Li, Zequn; Zheng, Shusen; Song, Penghong

doi:10.7150/ijbs.45420

Cited by 19 publications

(27 citation statements)

References 153 publications

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“…Since tumor cells produce energy through aerobic glycolysis (Warburg Effect) under hypoxia condition 12 , 13 , we examined the levels of pyruvate and lactate, the metabolites of glycolysis, as well as ATP content after the mitochondria were introduced into the melanoma cell media. The results exhibited that both pyruvate and lactate levels were reduced, accompanying with decreases of ATP content in the mitochondria-treated cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma

Hou

Zhou

et al. 2021

Int. J. Biol. Sci.

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Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.

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Section: Resultsmentioning

confidence: 99%

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma

Hou

Zhou

et al. 2021

Int. J. Biol. Sci.

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“…It is known that increasing evidence implicate altered DNA methylation in the pathophysiology of gestational diabetes mellitus (GDM) ( El Hajj et al, 2013 ; Reichetzeder et al, 2016 ; Dias et al, 2019 ) and a possible general defect in DNA methylation in diabetes is suggested ( Maier & Olek, 2002 ; Enquobahrie et al, 2015 ). WWOX gene is classified among the differentially methylated T2D susceptibility genes in adipose tissue ( Nilsson et al, 2014 ) and one of the targets of DNA methylation affecting the Warburg effect ( Zhu et al, 2020 ). Recent reports point to an important role of WWOX as one of the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in type 2 diabetics, simultaneously overlapping with the subnetwork of genes responsible for insulin secretion and insulin activity, measured by HOMA- β and HOMA-IR, respectively.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM)

Baryła

Płuciennik

Kośla

et al. 2021

PeerJ

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Background Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients. Methods Leukocytes were obtained from 135 pregnant women with (n = 98) or without (n = 37) GDM and, in turn, 3 months (n = 8) and 1 year (n = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (SLC2A1, SLC2A4), glycolytic pathway (HK2, PKM2, PFK, LDHA), Wnt pathway (DVL2, CTNNB1), and inflammatory response (NFKB1). Results GDM patients displayed a significant downregulation of WWOX with simultaneous upregulation of HIF1A which resulted in approximately six times reduction in WWOX/HIF1A ratio. As a consequence, HIF1A induced genes (SLC2A1, HK2, PFK, PKM) were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with WWOX/HIF1A ratio. The postpartum WWOX expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy. Conclusions The obtained results suggest a significant contribution of the WWOX gene to glucose metabolism in patients with gestational diabetes. Decreased WWOX expression in GDM compared to normal pregnancy, and in particular reduction of WWOX/HIF1A ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.

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“…DNA methylation has been described of specific key components in glycolytic pathways, glycolysis bypass pathways (i.e. gluconeogenesis and pentose phosphate pathway), as well as mitochondrial and oxygen sensing pathways ( 66 ). Furthermore many of the intermediates of cellular metabolic pathways participate in the chemical modifications that epigenetically modify DNA and histones ( 67 ).…”

Section: Epigenetic Changes In Tumors That Promote the Warburg Effectmentioning

confidence: 99%

“…Within the tumor, DNA methylation affects key glycolytic components, including glucose transporters (GLUT1, GLUT3), lactate dehydrogenase genes ( LDH-A, LDH-B ), the hexokinase 2 isoform (HK2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the pyruvate kinase (PK) isoform M2 (PKM2), each of which contribute to the Warburg effect ( 66 ). DNA hypermethylation-mediated inactivation of the Derlin-3 gene, which normally contributes to GLUT1 degradation, leads to increased GLUT1 expression ( 70 ).…”

Section: Epigenetic Changes In Tumors That Promote the Warburg Effectmentioning

confidence: 99%

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Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors

et al. 2021

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Reprogramming of metabolic priorities promotes tumor progression. Our understanding of the Warburg effect, based on studies of cultured cancer cells, has evolved to a more complex understanding of tumor metabolism within an ecosystem that provides and catabolizes diverse nutrients provided by the local tumor microenvironment. Recent studies have illustrated that heterogeneous metabolic changes occur at the level of tumor type, tumor subtype, within the tumor itself, and within the tumor microenvironment. Thus, altered metabolism occurs in cancer cells and in the tumor microenvironment (fibroblasts, immune cells and fat cells). Herein we describe how these growth advantages are obtained through either “convergent” genetic changes, in which common metabolic properties are induced as a final common pathway induced by diverse oncogene factors, or “divergent” genetic changes, in which distinct factors lead to subtype-selective phenotypes and thereby tumor heterogeneity. Metabolic heterogeneity allows subtyping of cancers and further metabolic heterogeneity occurs within the same tumor mass thought of as “microenvironmental metabolic nesting”. Furthermore, recent findings show that mutations of metabolic genes arise in the majority of tumors providing an opportunity for the development of more robust metabolic models of an individual patient’s tumor. The focus of this review is on the mechanisms governing this metabolic heterogeneity in breast cancer.

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How DNA methylation affects the Warburg effect

Cited by 19 publications

References 153 publications

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma

Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM)

Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors

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