The mechanistic link between various forms of cancer and cellular metabolism has eluded scientists for quite some time now. In particular, non-Hodgkin’s lymphomas represent a group of cancers where researchers have been trying to establish a metabolic connection.
Now, a collaboration led by scientists from the School of Medicine at The University of Texas Health Science Center at San Antonio has found evidence that directly links disrupted metabolism to diffuse large B-cell lymphoma (DLBCL), an often fatal type of cancer.
“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” stated senior author Ricardo Aguiar, M.D., Ph.D., associate professor of hematology-oncology in the School of Medicine at The University of Texas Health Science Center at San Antonio.
The findings from this study were published recently in Nature Communications through an article entitled “D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.”
Dr. Aquiar and his collaborators discovered the gene that encodes for the metabolic enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated within a subset of DLBCLs. This mutation causes lymphoma cells to become deficient in a key metabolite called alpha-ketoglutarate (α-KG).
“We have discovered a metabolic imbalance that is oncogenic or pro-cancer,” Dr. Aguiar said. “When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don’t function properly, resulting in a host of additional disturbances.”
Specifically, the enzyme isocitrate dehydrogenase (IDH) typically converts isocitrate to α-KG. However, it has been observed in some cancers that mutant IDH reduces α-KG to D2-hydroxygluturate (D2-HG), disrupting the dioxygenase enzymes.
In this study, the investigators found that the D2HGDH mutants in lymphoma were enzymatically inert. Moreover, the researchers were able to show that D2-HG was able to elevate intracellular levels of α-KG by modulating mitochondrial IDH expression and activity.
The role of D2HGDH in modulating IDH expression and consequently the cellular pool α-KG was an unexpected find for the research team. However, they were excited by their discovery and are looking for points along the new enzymatic pathways that can be exploited for chemotherapeutic intervention.
“Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and a-KG-mediated epigenetic remodeling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases,” concluded the scientists.