Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure

Ning Hou, Bo Ye, Xiang Li, Kenneth B. Margulies, Haodong Xu, Xuejun Wang, Faqian Li

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background-How canonical Wnt/β-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure. Methods and Results-We investigated canonical Wnt/β-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated cardiomyopathy, and murine desmin-related cardiomyopathy. Our data demonstrated that canonical Wnt/β-catenin signaling was activated through nuclear accumulation of β-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin-related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main β-catenin partner of the T-cell factor (TCF) family in adult hearts. We further revealed that c-Myc mRNA and protein levels were significantly elevated in failing hearts by real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. Immunoprecipitation and confocal microscopy further showed that β-catenin interacted and colocalized with TCF7L2. More importantly, chromatin immunoprecipitation confirmed that β-catenin and TCF7L2 were recruited to the regulatory elements of c-Myc. This recruitment was associated with increased histone H3 acetylation and transcriptional upregulation of c-Myc. With lentiviral infection, TCF7L2 overexpression increased c-Myc expression and cardiomyocyte size, whereas shRNA-mediated knockdown of TCF7L2 suppressed c-Myc expression and cardiomyocyte growth in cultured neonatal rat cardiomyocytes. Conclusions-This study indicates that TCF7L2 mediates canonic Wnt/β-catenin signaling and c-Myc upregulation during abnormal cardiac remodeling in heart failure and suppression of Wnt/β-catenin to c-Myc axis can be explored for preventing and treating heart failure.

Original languageEnglish (US)
Article numbere003010
JournalCirculation: Heart Failure
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2016

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T Cell Transcription Factor 1
Catenins
Up-Regulation
Heart Failure
Cardiac Myocytes
Desmin
Dilated Cardiomyopathy
Cardiomyopathies
Myocardial Ischemia
Proto-Oncogene Proteins c-myc
TCF Transcription Factors
myc Genes
Chromatin Immunoprecipitation
Acetylation
Immunoprecipitation
Confocal Microscopy
Histones
Small Interfering RNA
Reverse Transcription
Western Blotting

Keywords

  • acetylation
  • cardiomyopathy
  • cell signaling/signal transduction
  • desmin
  • heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure. / Hou, Ning; Ye, Bo; Li, Xiang; Margulies, Kenneth B.; Xu, Haodong; Wang, Xuejun; Li, Faqian.

In: Circulation: Heart Failure, Vol. 9, No. 6, e003010, 01.06.2016.

Research output: Contribution to journalArticle

Hou, Ning ; Ye, Bo ; Li, Xiang ; Margulies, Kenneth B. ; Xu, Haodong ; Wang, Xuejun ; Li, Faqian. / Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure. In: Circulation: Heart Failure. 2016 ; Vol. 9, No. 6.
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AU - Margulies, Kenneth B.

AU - Xu, Haodong

AU - Wang, Xuejun

AU - Li, Faqian

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AB - Background-How canonical Wnt/β-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure. Methods and Results-We investigated canonical Wnt/β-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated cardiomyopathy, and murine desmin-related cardiomyopathy. Our data demonstrated that canonical Wnt/β-catenin signaling was activated through nuclear accumulation of β-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin-related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main β-catenin partner of the T-cell factor (TCF) family in adult hearts. We further revealed that c-Myc mRNA and protein levels were significantly elevated in failing hearts by real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. Immunoprecipitation and confocal microscopy further showed that β-catenin interacted and colocalized with TCF7L2. More importantly, chromatin immunoprecipitation confirmed that β-catenin and TCF7L2 were recruited to the regulatory elements of c-Myc. This recruitment was associated with increased histone H3 acetylation and transcriptional upregulation of c-Myc. With lentiviral infection, TCF7L2 overexpression increased c-Myc expression and cardiomyocyte size, whereas shRNA-mediated knockdown of TCF7L2 suppressed c-Myc expression and cardiomyocyte growth in cultured neonatal rat cardiomyocytes. Conclusions-This study indicates that TCF7L2 mediates canonic Wnt/β-catenin signaling and c-Myc upregulation during abnormal cardiac remodeling in heart failure and suppression of Wnt/β-catenin to c-Myc axis can be explored for preventing and treating heart failure.

KW - acetylation

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KW - cell signaling/signal transduction

KW - desmin

KW - heart failure

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