Characterizing the role of nuclear pyruvate dehydrogenase upon mutant HRAS expression

Abstract

Oncogenic transformation can be caused by mutations in the Ras gene, present in 30% of all human cancers. Mutations in Harvey RAS (HRAS), an isoform of Ras, induce changes in metabolism, epigenome remodeling, and the transcriptome, enabling cells to grow and proliferate continuously. Cancer cells upregulate aerobic glycolysis to generate biosynthetic precursors necessary for rapid proliferation, called the Warburg effect. Additionally, glycolysis is important for histone acetylation, inducing an open chromatin structure. Earlier research showed that the mitochondrial enzyme pyruvate dehydrogenase (PDH) can produce acetyl-CoA in the nucleus, facilitating histone acetylation. This study investigates how PDH plays a role in the nucleus upon mutant HRAS expression. The findings demonstrate that when RPE cells express mutant HRASG12V, there is translocation of PDH to the nucleus. In the nucleus of mutant HRAS-induced cells, the interactome of PDH is reconfigured. The nuclear interactome of PDH includes enriched proteins involved in transcriptional regulation after mutant HRAS induction. Furthermore, PDH is located near the promotor regions of actively transcribed genes expressed after mutant HRAS transformation. Together, this might indicate that PDH could play a role in epigenome remodeling and gene transcription during mutant HRAS expression. Interference with nuclear PDH might offer therapeutic targets for cancer proliferation.