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Published on: April 5, 2015
Selective inhibition of yeast regulons by daunorubicin: a transcriptome-wide analysis
Marta Rojas1, Marta Casado, José Portugal
1Institut for Molecular Biology of Barcelona, IBMB-CSIC, Jordi Girona, 18, 08034 Barcelona, Spain. mrabmc@cid.csic.es <mrabmc@cid.csic.es>
Background:
The antitumor drug daunorubicin exerts some of its cytotoxic effects by binding to DNA and inhibiting the transcription of different genes. We analysed this effect in vivo at the transcriptome level using the budding yeast Saccharomyces cerevisiae as a model and sublethal (IC40) concentrations of the drug to minimise general toxic effects.
Results:
Daunorubicin affected a minor proportion (14%) of the yeast transcriptome, increasing the expression of 195 genes and reducing expression of 280 genes. Daunorubicin down-regulated genes included essentially all genes involved in the glycolytic pathway, the tricarboxylic acid cycle and alcohol metabolism, whereas transcription of ribosomal protein genes was not affected or even slightly increased. This pattern is consistent with a specific inhibition of glucose usage in treated cells, with only minor effects on proliferation or other basic cell functions. Analysis of promoters of down-regulated genes showed that they belong to a limited number of transcriptional regulatory units (regulons). Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin.
Conclusion:
The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks. This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.
Insights
The antitumor drug daunorubicin specifically inhibits glucose metabolism in yeast by altering gene expression. This daunorubicin effect suggests a potential therapeutic strategy against cancer cells, particularly under hypoxic conditions.
Area of Science:
- Molecular Biology
- Genomics
- Yeast Genetics
Background:
- Daunorubicin, an antitumor drug, inhibits gene transcription by binding to DNA.
- Understanding daunorubicin's precise molecular targets is crucial for optimizing cancer therapy.
- Budding yeast (Saccharomyces cerevisiae) serves as a model organism to study drug effects on gene expression.
Purpose of the Study:
- To investigate the in vivo effects of daunorubicin on the yeast transcriptome at sublethal concentrations.
- To identify specific genes and pathways affected by daunorubicin treatment.
- To elucidate the mechanism of daunorubicin-induced gene expression changes.
Main Methods:
- Transcriptome-wide analysis of gene expression in Saccharomyces cerevisiae treated with daunorubicin.
- Quantitative analysis of gene expression changes (up-regulation and down-regulation).
- Promoter analysis and data mining to identify affected transcriptional regulatory units and related transcription factors.
Main Results:
- Daunorubicin affected 14% of the yeast transcriptome, up-regulating 195 genes and down-regulating 280 genes.
- Down-regulated genes were primarily involved in glycolysis, the tricarboxylic acid cycle, and alcohol metabolism.
- Ribosomal protein gene transcription was unaffected or slightly increased, indicating specific inhibition of glucose metabolism with minimal impact on proliferation.
Conclusions:
- Daunorubicin treatment leads to specific inhibition of glucose metabolism in yeast.
- The drug likely impairs transcription factor binding to DNA, affecting regulatory networks.
- This mechanism may have therapeutic implications for hypoxic cancer cells.
