Selective inhibition of yeast regulons by daunorubicin: a transcriptome-wide analysis.
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.


CONCLUSIONS
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.
Rojas
Marta
M
Institut for Molecular Biology of Barcelona, IBMB-CSIC, Jordi Girona, 18, 08034 Barcelona, Spain. mrabmc@cid.csic.es <mrabmc@cid.csic.es>
Casado
Marta
M
Portugal
José
J
Piña
Benjamin
B
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004271:DNA, Fungal / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012331:RNA, Fungal / Q000235:genetics; D018085:Regulon / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D000970:Antineoplastic Agents; D004271:DNA, Fungal; D012331:RNA, Fungal; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003630:Daunorubicin