Oncometabolite d-2-hydroxyglutarate enhances gene silencing through inhibition of specific h3k36 histone demethylases

Abstract

Certain mutations affecting central metabolism cause accumulation of the oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors. High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases and Jumonji family of histone demethylases and cause epigenetic changes that lead to altered gene expression. The link between inhibition of DNA demethylation and changes in expression is strong in some cancers, but not in others. To determine whether D-2-hydroxyglutarate can affect gene expression through inhibiting histone demethylases, orthologous mutations to those known to cause accumulation of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae, which has histone demethylases but not DNA methylases or demethylases. Accumulation of D-2-hydroxyglutarate caused inhibition of several histone demethylases. Inhibition of two of the demethylases that act specifically on histone H3K36me2,3 led to enhanced gene silencing. These observations pinpointed a new mechanism by which this oncometabolite can alter gene expression, perhaps repressing critical inhibitors of proliferation.