Is this enzyme the key to the formation of highly malignant brain cancer?

There are many moving parts when it comes to the mechanics of how otherwise healthy cells are transformed into those that cause deadly cancers such as glioblastoma.

Research led by Zhimin Lu, Ph.D., professor of Neuro-Oncology at MD Anderson Cancer Center, has revealed new insight into how the enzyme RNF8 mediates the protein histone 3 (H3) to promote glycolysis and the formation of tumors. The results of the study were published in the May 15 online issue of the Journal of Experimental Medicine.

Lu’s team uncovered the role of RNF8-mediated H3 polyubiquitylation in the regulation of H3 stability and chromatin modification, paving the way to gene expression regulation and tumorigenesis (tumor formation).

“Disassembly of nucleosomes in which genomic DNA is packaged with histone regulates gene expression. However, the mechanisms underlying nucleosome disassembly for gene expression remain elusive,” said Lu. “We showed that activation of epithelial growth factor receptor (EGFR), which is overexpressed or mutated in nearly 60 percent of glioblastomas, results in pyruvate kinase muscle isozyme M2 (PKM2)-dependent binding of RNF8 to histone H3. RNF8 mediates H3 polyubiquitylation, leading to proteasome-dependent H3 degradation.”

In addition, H3 polyubiquitylation induces histone dissociation from chromatin, nucleosome disassembly, and binding of RNA polymerase II to MYC and CCND1 promoter regions for transcription.

“Thus, RNF8-mediated H3 polyubiquitylation promotes tumor cell glycolysis and proliferation and brain tumorigenesis,” he said.

“This suggests that receptor tyrosine kinase activation-accelerated cell growth and proliferation require disassembly of nucleosomes and a rapid turnover of histones so that the gene transcriptional machinery is maintained at a highly active state,” said Lu. “Given the broad effect of the enzyme PKM2 on gene expression by acting as a co-activator of transcriptional factors, these findings highlight the instrumental role of PKM2/RNF8-mediated modification, which is instrumental for epigenetic regulation of gene expression and tumorigenesis.”

MD Anderson team members included Yan Xia, Ph.D.; Xinjian Li, Ph.D.; Yugang Wang, Ph.D.; Yanhua Zheng, Ph.D.; and Jong-Ho Lee, Ph.D. Participating institutions included Shanghai Institute for Biological Sciences, Shanghai, China; Shanghai Jiaotong University, Shanghai, China; and Ocean University of China, Qingdao, China.