Abstract
WHSC1L1/NSD3, one of the most aggressive human oncogenes, has two isoforms derived from alternative splicing. Overexpression of long or short NSD3 is capable of transforming a healthy into a cancer cell. NSD3s, the short isoform, contains only a PWWP domain, a histone methyl-lysine reader involved in epigenetic regulation of gene expression. With the aim of understanding the NSD3s PWWP domain role in tumorigenesis, we used Saccharomyces cerevisiae as an experimental model. We identified the yeast protein Pdp3 that contains a PWWP domain that closely resembles NSD3s PWWP. Our results indicate that the yeast protein Pdp3 and human NSD3s seem to play similar roles in energy metabolism, leading to a metabolic shift toward fermentation. The swapping domain experiments suggested that the PWWP domain of NSD3s functionally substitutes that of yeast Pdp3, whose W21 is essential for its metabolic function.
Highlights
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation [1]
Yeast strains were grown in glycerol, a carbon source that favors oxidative respiration, so the yeast metabolic phenotype could resemble that of a mammalian healthy cell
NSD3s+ cells exhibited a decrease in oxygen consumption when compared to WT cells (Figure 1B), indicating that overexpression of NSD3s is capable of decreasing cell respiratory capacity leading to a faster proliferation
Summary
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation [1]. Even though no specific gene mutation or chromosomal abnormality is common to all cancers, most cancers express aerobic fermentation (Warburg effect), regardless of their tissue or cellular origin [6], which is a robust metabolic hallmark of most tumors. Seyfried [1], several reports correlate respiratory dysfunction and mitochondrial structural defects to abnormalities in DNA repair mechanisms and the upregulation of fermentation pathways [7, 8], leading to carcinogenesis. This evidence supports the idea that cancer is a disease of metabolic origins. Some mutations enable cancer cells to acquire and metabolize nutrients in a way that favors proliferation rather than efficient ATP production [10, 11]
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