Oncotarget

Research Papers:

The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes

Shu-Ting Liu _, Shih-Ming Huang, Ching-Liang Ho, Li-Chen Yen, Chi-Jung Huang, Wei-Shiang Lin and James Yi-Hsin Chan

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Oncotarget. 2015; 6:37443-37457. https://doi.org/10.18632/oncotarget.5338

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Abstract

Shu-Ting Liu1,2,*, Shih-Ming Huang1,*, Ching-Liang Ho2,*, Li-Chen Yen1, Chi-Jung Huang1,3, Wei-Shiang Lin4, James Yi-Hsin Chan5,6

1Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, Republic of China

2Department of Medicine, Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China

3Department of Medical Research, Cathay General Hospital, New Taipei City 221, Taiwan, Republic of China

4Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan, Republic of China

5Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan, Republic of China

6Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China

*These authors have equally contributed to this work

Correspondence to:

James Yi-Hsin Chan, e-mail: jchan9473@gmail.com

Keywords: doxorubicin, cardio-toxicity, myogenin, mRNA expression profile, gene regulation

Received: June 05, 2015     Accepted: September 25, 2015     Published: October 07, 2015

ABSTRACT

Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression.


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