Mechanism of anthracycline-mediated down-regulation of GATA4 in the heart.

AIMS Anthracyclines such as daunorubicin (DNR) and doxorubicin are effective cancer chemotherapeutic agents, but can induce cardiotoxicity. GATA4 has been shown to serve as a survival factor of cardiac muscle cells, and anthracyclines promote apoptosis in part by down-regulating GATA4. The present study investigated the mechanism of anthracycline action to down-regulate GATA4. METHODS AND RESULTS DNR inhibited the transcriptional activity exhibited by the 250 bp conserved region immediately upstream from the transcriptional start site of the Gata4 gene. Mapping this region identified that the CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) binding to the CCAAT box was inhibited by DNR in HL-1 cardiac muscle cells and in perfused isolated mouse hearts. The DNR action on the Gata4 promoter was found to be dependent on p53, since DNR promoted nuclear binding of p53 to CBF/NF-Y and pifithrin-α (a p53 inhibitor) attenuated DNR down-regulation of GATA4. CONCLUSION Anthracycline down-regulation of GATA4 is mediated by the inhibition of Gata4 gene transcription via a novel mechanism that involves the p53-dependent inhibition of CBF/NF-Y binding to the CCAAT box within the Gata4 promoter.