2-Hydroxyglutarate: Impact on Cancer and Metabolism

Alterations in cellular metabolism play a significant role in cancer development, with certain metabolites acting as key regulators of disease progression. One such metabolite, 2-hydroxyglutarate (2-HG), has gained attention for its involvement in tumor biology and metabolic dysregulation.

Biochemical Formation

2-HG arises as a byproduct of cellular metabolism, primarily through aberrant enzymatic activity. Under normal conditions, the tricarboxylic acid (TCA) cycle maintains a balance of intermediates for energy production and biosynthesis. However, mutations in isocitrate dehydrogenase (IDH) enzymes, particularly IDH1 and IDH2, lead to pathological 2-HG accumulation. These mutations convert α-ketoglutarate (α-KG) into 2-HG instead of succinyl-CoA. This neomorphic activity results in millimolar concentrations of 2-HG, far exceeding physiological levels.

Beyond IDH mutations, 2-HG can accumulate under metabolic stress, such as hypoxia or mitochondrial dysfunction. In these conditions, the normal redox balance is disrupted, increasing α-KG reduction to 2-HG by lactate dehydrogenase (LDH) and malate dehydrogenase (MDH). This non-mutational route is particularly relevant in rapidly proliferating cells. The two enantiomers of 2-HG—D-2-HG and L-2-HG—have distinct sources and effects. IDH mutations primarily generate D-2-HG, while L-2-HG accumulation is often linked to deficiencies in L-2-hydroxyglutarate dehydrogenase, the enzyme responsible for its degradation.

Role As An Oncometabolite

The buildup of 2-HG in cancer cells disrupts epigenetic and metabolic processes, enhancing tumorigenic potential. D-2-HG, produced by mutant IDH enzymes, competitively inhibits α-KG-dependent dioxygenases, enzymes that regulate histone and DNA demethylation. This inhibition affects ten-eleven translocation (TET) enzymes and Jumonji-C domain-containing histone demethylases, leading to widespread hypermethylation. These changes contribute to an undifferentiated cellular state, a hallmark of aggressive tumors such as gliomas and acute myeloid leukemia (AML).

Genome-wide methylation profiling of IDH-mutant tumors has revealed a CpG island methylator phenotype (CIMP), which silences tumor suppressor genes while sustaining pro-proliferative pathways. In gliomas, this prevents neural precursor cells from differentiating, while in AML, it locks hematopoietic progenitors in an immature state, fostering leukemic expansion.

Beyond epigenetics, 2-HG also influences cellular signaling. By inhibiting prolyl hydroxylases, which require α-KG, 2-HG stabilizes hypoxia-inducible factor (HIF), a transcription factor that promotes glycolysis and angiogenesis. This metabolic shift, known as the Warburg effect, provides cancer cells with biosynthetic precursors while minimizing oxidative phosphorylation. The interplay between 2-HG accumulation, HIF activation, and metabolic adaptation supports tumor growth.

Key Influences On Cellular Metabolism

2-HG accumulation disrupts metabolic homeostasis by interfering with α-KG-dependent enzymes. This inhibition distorts the TCA cycle, leading to imbalances in key intermediates and forcing cells to reroute metabolic fluxes. The shift from oxidative phosphorylation to glycolysis supports rapid proliferation but reduces mitochondrial efficiency.

In cancer cells, this metabolic shift reinforces a glycolytic phenotype. Suppressed oxidative metabolism increases reliance on glucose and glutamine for ATP production and biosynthesis. The heightened demand for glutamine, or glutamine addiction, arises from the need to replenish TCA cycle intermediates. Additionally, 2-HG alters amino acid metabolism, affecting nitrogen balance and impacting nucleotide synthesis and redox stability.

Dysregulated redox homeostasis is another consequence of 2-HG accumulation. Its production affects NADH/NAD+ and FADH2/FAD ratios, increasing reactive oxygen species (ROS). Elevated ROS levels can either activate stress response pathways that promote tumor survival or create vulnerabilities that make cancer cells more susceptible to therapy.

Detection And Measurement Approaches

Accurately quantifying 2-HG is crucial for both diagnostics and research. Due to its structural similarity to other TCA cycle intermediates, advanced analytical techniques are required. Mass spectrometry (MS), particularly liquid chromatography-tandem mass spectrometry (LC-MS/MS), is the gold standard, as it differentiates between D- and L-2-HG. This distinction is critical since D-2-HG is linked to IDH mutations, while L-2-HG often results from metabolic stress.

Magnetic resonance spectroscopy (MRS) provides a non-invasive alternative for real-time metabolic profiling in IDH-mutant gliomas. Proton (^1H)-MRS can detect elevated 2-HG in brain tumors, aiding diagnosis and treatment monitoring. However, its resolution and specificity are limited, particularly at low concentrations or when overlapping spectral signals interfere with quantification. Advances in high-field MRI scanners and optimized acquisition protocols have improved detection capabilities.

Associations With Different Cancers

2-HG accumulation is implicated in multiple cancers, particularly those with IDH mutations, where it influences disease progression and therapeutic responses.

Gliomas

IDH-mutant gliomas exhibit some of the highest 2-HG levels, distinguishing them from IDH-wildtype glioblastomas. Elevated 2-HG disrupts DNA and histone demethylation, creating a CpG island hypermethylation phenotype (G-CIMP) that alters gene expression. This hypermethylation pattern is associated with a better prognosis than IDH-wildtype glioblastomas but also presents therapeutic vulnerabilities. Additionally, 2-HG stabilizes HIFs, reinforcing a glycolytic phenotype that supports glioma proliferation.

Acute Myeloid Leukemia (AML)

IDH mutations are frequently detected in AML, where they impair normal myeloid differentiation by inhibiting TET enzymes responsible for DNA demethylation. This hypermethylation locks hematopoietic progenitors in an undifferentiated state, promoting leukemic expansion. IDH-mutant AML represents a distinct molecular subset, often co-occurring with NPM1 or FLT3 mutations. 2-HG serves as a metabolic biomarker, aiding in disease classification and treatment stratification. Targeted IDH inhibitors, such as enasidenib (IDH2 inhibitor) and ivosidenib (IDH1 inhibitor), have shown clinical efficacy in restoring normal differentiation by reducing 2-HG levels.

Cholangiocarcinoma

IDH mutations and 2-HG accumulation also occur in intrahepatic cholangiocarcinoma, a bile duct malignancy. Though less common than in gliomas or AML, these tumors exhibit a hypermethylation phenotype similar to other IDH-mutant cancers. 2-HG-driven epigenetic reprogramming alters cell fate, contributing to tumor initiation and progression. Given its role in oncogenesis, IDH inhibitors have been explored as potential treatments, with early clinical trials showing promising responses in patients with IDH1 mutations.