Many of us have been lectured by our dentist about eating those delicious, sticky candies. Now, as it turns out, those cavity-causing sugars not only stick to your teeth but can stick to your histones too! Through a non-enzymatic process known as glycation, a glucose group is covalently attached to specific amino acids, which can be further rearranged to form cross-links. These cross-linked glycation end-products have been implicated in diabetes and cancer, and new research from the lab of Yael David (Memorial Sloan Kettering, USA) may give us insight as to how. Thankfully, the team also unveils the cellular dentist: the DJ-1 enzyme, which can remove those sticky glycations.
In collaboration with the labs of Shixin Liu (Rockefeller Institute, USA) and Sarat Chandarlapaty (Memorial Sloan Kettering, USA), the team set out to characterize histone glycation by methylglyoxal (MGO), a cytotoxic metabolite known to glycate other proteins. They specifically looked at the effect on nucleosome formation and chromatin architecture using a clever combination of SDS-PAGE glycation readouts, chromatin precipitation assays, and even single-molecule optical tweezers. After moving through biochemical and live cell assays, they also analyzed breast cancer models using mouse xenografts as well as primary tumor samples.
Here are the sweet details:
- MGO primarily glycates histones H3 and H4 and interferes with normal epigenetic modifications (acetylation and methylation)
- Glycation of H3 and H4 disrupts nucleosome formation
- MGO can also glycate nucleosomal DNA, potentially cross-linking histones to DNA
- This increases nucleosome stability and chromatin compaction while decreasing DNA accessibility
- The enzyme DJ-1 deglycates histones in vitro and in live cells
- Knockdown of DJ-1 results in increased sensitivity to MGO and decreased cell viability
- Breast cancer cell lines have increased basal histone glycation, as well as increased DJ-1 levels
The seemingly paradoxical increase of both DJ-1 and histone glycation in cancer cells prompted the authors to hypothesize that cancer cells may be dependent on increased DJ-1 levels to decrease cellular stress and evade cell death. In support of this, other studies have shown that knockdown of DJ-1 in cancer cells results in cell death, making DJ-1 a tempting therapeutic target for cancer treatment.
4 out of 5 (cellular) dentists recommend you read the full article in Nature Communications, March 2019.