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.
Highlights
Among the biggest surprises from cancer genome sequencing has been the extent to which mutations affecting metabolic enzymes appear as drivers of specific types of cancers
To study the impact of Isocitrate dehydrogenases (IDH) mutations on gene expression, an analogous tumor-associated IDH mutation was made in Saccharomyces cerevisiae (IDP2-R132H) at the IDP2 locus
Heterochromatic gene silencing at the HML locus was used as the assay for detecting changes in gene expression of a locus for which the transcriptional state is epigenetically inherited using the Cre-Reported Altered States of Heterochromatin (CRASH) assay
Summary
Among the biggest surprises from cancer genome sequencing has been the extent to which mutations affecting metabolic enzymes appear as drivers of specific types of cancers. Specific IDH mutations are highly prevalent features of certain subsets of cancers, including 60–90% of gliomas and secondary glioblastomas, 20% of late-stage acute myelogenous leukemia, ~50% of central and periosteal cartilagenous tumors, and 10–20% of interhepatic cholangiocarcinoma (Parsons et al, 2008; Molenaar et al, 2014). The high frequency and patterns of IDH mutations suggest that they are important in early tumor development. In the case of acute myelogenous leukemia, IDH mutations contribute to progression of these tumors (Molenaar et al, 2014; Reitman and Yan, 2010). IDH mutations in tumors occur exclusively as heterozygous missense mutations. The most frequently documented IDH mutations occur as substitutions of arginine 132 in IDH1 or the equivalent arginine (172) in IDH2. The specific amino acid substitution varies across and within tumor subtypes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
