Figure 6.

Protein NECMs as a new mechanistic link between microenvironmental stress and cell fate. Abrogated metabolism and mutational stress (for example, in NECM repair enzymes) promote accumulation of NECMs on histones. These adducts disrupt histones’ other regulatory enzymatic modifications, altering the epigenetic landscape, thus leading to changes in the cellular transcriptome and inducing transformation. Diseased cells, in turn, increase metabolic stress (through increased glycolysis in cancer, for example), generating reactive metabolites and oxygen species that further drive this cycle.