The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism

Abstract

Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O 2 -dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type.

HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

“…Given the association with congenital cardiac anomalies, we propose a baseline echocardiogram investigation is undertaken with cardiology follow‐up dependent upon findings. Although HIST1H1E somatic variants have been associated with chronic lymphocytic leukemia as well as diffuse large B‐cell lymphoma and hepatocellular carcinoma, these are more usually nonsynonymous variants distributed throughout the gene (Chang, Yim, & Park, ). None of the patients in this current clinical series developed cancer.…”

A three layered histone epigenetics in breast cancer metastasis

“…However, in presence of AKT inhibitor KDM5A translocate to nucleus and demethylates H3K4. Histone demethylase JARID1A/B are oncogenes, highly expressed in breast cancer condition [125]. They interact with pRB by demethylation of H3K4 [125].…”

The rapidly changing landscape in mature T‐cell lymphoma (MTCL) biology and management

“…Biochemically, wild-type IDH2 converts isocitrate to α-ketoglutarate (α-KG), which is a critical cofactor in α-KG-dependent enzymes (oxidative demethylases) such as TET2 and KDM, which normally promote demethylation of DNA and histone proteins. 23,24 Mutant IDH2 converts isocitrate to R-2-hydroxyglutarate, which impairs α-KGdependent enzymes, leading to increased genome-wide methylation. 19 Inactivating mutations in the ten-eleven translocation-2 (TET2) gene have also been identified in MTCL and in patients with AML.…”