Elevated
            <scp>d</scp>
            -2-hydroxyglutarate during colitis drives progression to colorectal cancer

Han, Jie; Jackson, Dakota N.; Holm, Janette; Turner, Kevin; Ashcraft, Paula; Wang, Xuan; Cook, Beth N; Arning, Erland; Genta, Robert M.; Venuprasad, K.; Souza, Rhonda F.; Sweetman, Lawrence; Theiss, Arianne L.

doi:10.1073/pnas.1712625115

Cited by 42 publications

(41 citation statements)

References 34 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…D2HGDH transcriptional regulation studies in colorectal cancer have recently been reported (Han et al, ). These investigators identified a putative Hif‐1α transcription factor binding site in the D2HGDH promoter, suggesting that Hif‐1α controls both the expression of D‐2‐HGDH as well as D‐2‐HG levels.…”

Section: Discussionmentioning

confidence: 99%

D‐2‐hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants

et al. 2019

View full text Add to dashboard Cite

D‐2‐hydroxyglutaric aciduria Type I (D‐2‐HGA Type I), a neurometabolic disorder with a broad clinical spectrum, is caused by recessive variants in the D2HGDH gene encoding D‐2‐hydroxyglutarate dehydrogenase (D‐2‐HGDH). We and others detected 42 potentially pathogenic variants in D2HGDH of which 31 were missense. We developed functional studies to investigate the effect of missense variants on D‐2‐HGDH catalytic activity. Site‐directed mutagenesis was used to introduce 31 missense variants in the pCMV5‐D2HGDH expression vector. The wild type and missense variants were overexpressed in HEK293 cells. D‐2‐HGDH enzyme activity was evaluated based on the conversion of [2H4]D‐2‐HG to [2H4]2‐ketoglutarate, which was subsequently converted into [2H4]L‐glutamate and the latter quantified by LC‐MS/MS. Eighteen variants resulted in almost complete ablation of D‐2‐HGDH activity and thus, should be considered pathogenic. The remaining 13 variants manifested residual activities ranging between 17% and 94% of control enzymatic activity. Our functional assay evaluating the effect of novel D2HGDH variants will be beneficial for the classification of missense variants and determination of pathogenicity.

show abstract

Section: Discussionmentioning

confidence: 99%

D‐2‐hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Indeed, D‐2‐HG is involved in epigenetic alteration (Sciacovelli & Frezza, ; Dang & Su, ; Janke, Iavarone, & Rine, ), dysregulation of ROS production and stabilization of HIF‐1 (Collins et al , ), inhibition of α‐ketoglutarate‐dependent and non‐heme iron‐dependent dioxygenases, including members of the alkylated DNA repair protein (AlkB) family, such as ALKBH2 and ALKBH3 (Chen et al , ), metabolic dysregulation and impairment of cell differentiation (Bezawork‐Geleta et al , ; Dang & Su, ) and avoidance of the immune system (Lucca & Hafler, ). Furthermore, a recent report suggests that 2‐HG can also be involved in the progression from colitis to colon cancer, and the detection of this oncometabolite in the urine can be considered a valuable diagnostic tool to identify patients at risk for cancer development (Han et al , ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

View full text Add to dashboard Cite

Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

show abstract

“…HIF-1α associates with hypoxia response element (HRE), forming the response element binding protein and activating the formation of complexes of other transcription factors. HIF-1α has been revealed to upregulate expression of VEGF and bFGF (24,25), and upregulation of HIF-1α in CRC tissues during hypoxic conditions enabled the survival of tumor cells and potentiated evolution of tumors (26,27). Proliferation of endothelial cells underlies the formation of blood vessels and thus is required for angiogenesis, both physiologically and pathophysiologically in tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colorectal cancer

et al. 2020

View full text Add to dashboard Cite

Tumor angiogenesis is an important factor which precipitates recurrence and metastasis of colorectal cancer (CRC). Angiogenesis is also a significant feature which accompanies invasion and metastasis of CRC. Tumor hypoxia activates hypoxia inducible factor (HIF), which promotes angiogenesis in CRC. HIF significantly promotes cell proliferation and angiogenesis in CRC, facilitating invasion and metastasis. Tanshinone IIA (Tan IIA) has been revealed to effectively inhibit angiogenesis in CRC, although the underlying mechanism remains to be determined. The aim of the present study was to determine the effects of HIF-1α on hypoxia induced angiogenesis in CRC cells, the effects of Tan IIA on the expression of pro-angiogenic factors in CRC cells, and on human umbilical vein endothelial cell (HUVEC) tube formation in normal and hypoxic conditions. The results of the present study revealed that Tan IIA not only decreased HIF-1α expression and inhibited the secretion level of vascular endothelial growth factor and basic fibroblast growth factor, but also efficiently decreased proliferation, tube formation and metastasis of HUVECs. The results highlight the potential of Tan IIA-mediated targeting of HIF-1α as a potential therapeutic option for treatment of patients with CRC.

show abstract

Elevated d -2-hydroxyglutarate during colitis drives progression to colorectal cancer

Cited by 42 publications

References 34 publications

D‐2‐hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants

D‐2‐hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants

Oncometabolites in cancer aggressiveness and tumour repopulation

Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colorectal cancer

Contact Info

Product

Resources

About