The PWWP domain of the human oncogene WHSC1L1/NSD3 induces a metabolic shift toward fermentation

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.

1H NMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in Saccharomyces cerevisiae

“…7 The PWWP domain acts as a chromatin modification reader by recognizing both DNA and histone methylated lysines at the level of the nucleosome. 19 We concluded that NSD3s-PWWP functionally substitutes Pdp3-PWWP, suggesting that NSD3s and Pdp3 play similar roles in energy metabolism. Despite the low sequence similarity, they are highly similar in 3D conformation, as showed by ab initio modeling.…”

“…Breast cancer patients display increased plasma BCAA levels, even when the branched-chain amino acid transaminase 1, enzyme that participates in BCAA catabolism (Figure 4), is expressed. 19 Tumor cells exhibit high glutamine consumption, which is used as the main substrate for anaplerosis. 41 Valine levels are elevated in endomentrial 40 and breast 41 cancers.…”

“…The analysis was done on GraphPad Prism 6.0, with a confidence level of 95%.3 | RESULTSPreviously, we demonstrated that overexpression of Pdp3 or NSD3s in S cerevisiae, cultured under oxidative metabolism, led to an increase in growth rate and sensitivity to reactive oxygen species, while decreasing oxygen consumption 19. The analysis was done on GraphPad Prism 6.0, with a confidence level of 95%.3 | RESULTSPreviously, we demonstrated that overexpression of Pdp3 or NSD3s in S cerevisiae, cultured under oxidative metabolism, led to an increase in growth rate and sensitivity to reactive oxygen species, while decreasing oxygen consumption 19.…”

“…Three-dimensional structures of protein complexes formed by the Royal family members reveal that the N-terminal β-barrel is responsible for methylated lysine recognition and histone binding, which are essential for epigenetic regulation. 19 Overexpression of both Pdp3 and NSD3s in S cerevisiae induces a shift from oxidative to fermentative metabolism, a hallmark of cancer. 17,18 Previously, we have demonstrated that the PWWP domains of Pdp3 and NSD3s share 25% sequence identity.…”

“…17,18 Previously, we have demonstrated that the PWWP domains of Pdp3 and NSD3s share 25% sequence identity. 19 NSD3s and Pdp3 induce similar metabolic phenotypes in S cerevisiae; however, to confirm this functional relationship, it is necessary to elucidate the metabolic pathways leading to the observed phenotypical change. 19 Overexpression of both Pdp3 and NSD3s in S cerevisiae induces a shift from oxidative to fermentative metabolism, a hallmark of cancer.…”