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

• Published in: Cardiovascular research 2011-04, Vol.90 (1), p.97-104
• Main Authors: PARK, Ah-Mee, NAGASE, Hiroko, LINGLING LIU, VINOD KUMAR, Shilpashree, SZWERGOLD, Nava, WONG, Chi-Ming, SUZUKI, Yuichiro J
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - toxicity; Base Sequence; Benzothiazoles - pharmacology; Binding Sites; Biological and medical sciences; Cardiology. Vascular system; CCAAT-Binding Factor - metabolism; Cell Line; Daunorubicin - toxicity; Down-Regulation; GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Original; Perfusion; Promoter Regions, Genetic - drug effects; Time Factors; Toluene - analogs & derivatives; Toluene - pharmacology; Transcription, Genetic - drug effects; Transfection; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvq361

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. 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. 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.