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Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival

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Abstract

The nuclear acetyltransferase p300 is rapidly and stably induced in the heart during hemodynamic stress, but the mechanism of this induction is unknown. To determine the role of oxidative stress in p300 induction, we exposed neonatal rat cardiac myocytes to doxorubicin (DOX, 1 μM) or its vehicle, and monitored p300 protein content and stability for 24 h. Levels of p300 rose substantially within 1 h and remained elevated for at least 24 h, while p300 transcript levels declined. In the presence of cycloheximide, the estimated half-life of p300 in control cells was approximately 4.5 h, typical of an immediate-early response protein. DOX treatment prolonged p300 t1/2 to >24 h, indicating that the sharp rise in p300 levels was attributable to rapid protein stabilization. p300 stabilization was entirely due to an increase in acetylated p300 species with greatly enhanced resistance to proteasomal degradation. The half-life of p300 was dependent on its acetyltransferase activity, falling in the presence of p300 inhibitors curcumin and anacardic acid, and increasing with histone deacetylase (HDAC) inhibition. At the same time, acetyl-STAT3, phospho-STAT3-(Tyr 705) and -(Ser 727) increased, together with a prolongation of STAT3 half-life. SiRNA-mediated p300 knockdown abrogated all of these effects, and strongly enhanced DOX-mediated myocyte apoptosis. We conclude that DOX induces an acute amplification of p300 levels through auto-acetylation and stabilization. In turn, elevated p300 provides a key defense against acute oxidative stress in cardiac myocytes by acetylation, activation, and stabilization of STAT3. Our results suggest that HDAC inhibitors could potentially reduce acute anthracycline-mediated cardiotoxicity by promoting p300 auto-acetylation.

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Acknowledgments

The authors are grateful to Dr. Paul Kurlansky for insightful comments on the text. This study was supported by grants from the National Institutes of Health (NHLBI R01- HL71094 to N.H.B.) and the Florida Heart Research Institute (to N.H.B.), and an American Heart Association Greater Southeastern Affiliate Predoctoral Fellowship award (to S.J.).

Conflict of interest

None of the authors has any financial or other conflict of interest relative to the material presented in this manuscript.

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  1. Department of Medicine, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, 33101, USA

    Jianqin Wei, Lindsay R. Mitrani & Nanette H. Bishopric

  2. Departments of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33101, USA

    Nanette H. Bishopric

  3. Departments of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33101, USA

    Sumit Jain

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  1. Sumit Jain
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Jain, S., Wei, J., Mitrani, L.R. et al. Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival. Breast Cancer Res Treat 135, 103–114 (2012). https://doi.org/10.1007/s10549-012-2069-6

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