HOUSTON - A metabolic protein that nourishes cancer cells also activates tumor-promoting genes by loosening part of the packaging that entwines DNA to make up chromosomes, a team led by scientists at The University of Texas MD Anderson Cancer Center reports in the Aug. 16 issue of Cell.
Working in cell lines and mouse models of glioblastoma multiforme, the most lethal form of brain tumor, senior author Zhimin Lu, Ph.D., associate professor of Neuro-Oncology at MD Anderson, and colleagues show that pyruvate kinase M2 (PKM2) fuels tumor growth by influencing a histone protein.
DNA is packaged in and spooled around histone proteins. The researchers found that PKM2 tags histone H3 with a phosphate group (one atom of phosphorous, four of oxygen) in a specific location called T11.
'No phosphorylation of H3, no tumor'
This phosphorylation leads to activation of the tumor-promoting genes, increased tumor cell reproduction and formation of tumors, Lu said. "If there's no phosphorylation of H3, there's no tumor. It's that crucial to glioblastoma formation."
An analysis of 85 human glioblastomas indicated that higher levels of PKM2 expression in the cell nucleus and of H3 phosphorylation are correlated with shorter survival. A separate analysis showed higher levels of H3 phosphorylation associated with higher grade tumors in a comparison of 30 low-grade tumor samples and 45 high grade glioblastomas.
"Histone 3-T11 phosphorylation has great potential to serve as both a prognostic marker and a guide for the use of PKM2-inhibiting therapies once they are developed," Lu said.
PKM2 has long been known for its well-established role in aerobic glycolysis - the processing of glucose into energy that solid tumors, glioblastomas in particular, rely on heavily to survive and grow. Lu and colleagues have been teasing out the mechanisms of PKM2's other role - the transcription and activation of genes.
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center