A flurry of studies over recent years has revealed a significant link between mutations in histone H3 genes and tumorigenesis, although how such H3 mutations (or “oncohistones”) mediate tumorigenesis had only been assessed in certain brain tumors.
However, two new studies in Science have now revealed how oncohistones can promote tumorigenesis in mesenchymal tissues, which includes bone- and cartilage-producing cells. They focused on the presence of a histone H3 mutation in chondroblastomas (bone tumors comprised of cartilage-producing chondroblasts cells) which may arise from abnormal mesenchymal progenitor cell (MPC) expansion.
- A histone H3 lysine-36-to-methionine (H3K36M) mutation disrupts murine MPC gene expression profiles and inhibits MPC differentiation
- injection of mutated MPCs into immunodeficient mice causes tumorigenesis
- The H3K36M mutation inhibited H3K36 methyltransferase activity
- This reduced H3K36 methylation and, as a consequence, increased methylation of the nearby H3K27 at intergenic regions
- This redistributed the Polycomb repressive complex 1 (PRC1) away from H3K27 at repressed gene regulatory regions and led to the aberrant activation of genes which block MPC differentiation
The second study from the lab of Zhiguo Zhang found some similar patterns in their study focused on chondroblastomas and chondrocytes themselves.
- H3K36M mutation in chondrocyte/chondroblastoma cells led to reduced levels of H3K36 methylation mediated by H3K36 methyltransferase inhibition
- H3K36M mutation also led to altered gene expression
- Such genes, as well as genes with altered levels of H3K36 methylation, were associated with tumorigenesis-associated pathways
- H3K36M chondrocytes exhibited several hallmarks of tumorigenesis
- Increased stemness, reduced apoptosis, and defects in differentiation.
Overall, these studies suggest that single mutations in the histone H3 gene can produce oncohistones with the ability to alter cellular epigenetic landscapes, promote tumorigenesis-associated gene expression, and thereby promote mesenchymal tumorigenesis.