Abstract
Valproic acid (VA) is a pharmacologically important histone deacetylase inhibitor that recently garnered attention as an anticancer agent. Since the molecular mechanisms behind the multiple effects of VA are unclear, this study was aimed to unravel the comprehensive cellular processes affected by VA and its molecular targets in vivo using budding yeast as a model organism. Interestingly, genome-wide transcriptome analysis of cells treated with VA showed differential regulation of 30% of the genome. Functional enrichment analysis of VA transcriptome evidenced alteration of various cellular processes including cell cycle, cell wall biogenesis, DNA repair, ion homeostasis, metabolism, stress response, transport and ribosomal biogenesis, etc. Moreover, our genetic screening analysis revealed VA molecular targets belonging to oxidative and osmotic stress, DNA repair, cell wall integrity, and iron homeostasis. Further, our results demonstrated the activation of mitogen-activated protein kinases (MAPKs) Hog1 (p38) and Slt2 (p44/42) upon VA treatment. Our results also exhibited that VA acts through alteration of mitochondrial, ER architecture and functions. Especially, VA effects were neutralized in cells lacking lipid particles. Altogether, our results deciphered the novel molecular insights and mechanistic links to strengthen our knowledge on diverse cellular effects of VA along with its probable therapeutic targets and detoxification approaches.
Highlights
Our transcriptome and genetic screening results revealed diverse cellular processes targeted by Valproic acid (VA) in addition to new molecular targets that belonging to cell wall biogenesis, metal homeostasis, oxidative stress and DNA repair are essential for mediating its effects and tolerance
Cells treated with VA for 3 h failed to show methylene blue (MB) stained cells, are metabolically active at the highest dose tested (Fig. S1a) and suggests that the growth inhibition by VA might be credited to cell arrest and not cell death
We investigated the molecular mechanisms that VA perturbs to mediate its effects by global transcriptional profiling and target genes that are required for VA tolerance by chemical genetics approach using budding yeast as a model organism
Summary
The HDACs9 and glycogen synthase kinase-3 (GSK3)[10] are the known targets of VA, the molecular mechanisms and genetic targets responsible for multiple effects of VA and its toxicity are unclear. The present study aimed to identify the underlying mechanisms of VA induced effects in vivo through chemical genetics and global transcriptomics approach using budding yeast Saccharomyces cerevisiae, which offers a robust model organism to unravel the conserved molecular targets and mode of action of bioactive molecules, toxicants and pollutants[11]. Our results facilitate us to understand the response of eukaryotic cells to VA in vivo and identify plausible diverse molecular mechanisms, targets and its mode of action
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