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



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.



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.
Department of Pharmacology, Guangzhou Medical University, Guangzhou, PR China.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
Ning
N
Hou
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.|Department of Laboratory Medicine and Pathology, University of Minnesota, Room 293, Dwan Variety Club Cardiovascular Research Center, 425 E River Pkwy, Minneapolis, MN.
Bo
B
Ye
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
Xiang
X
Li
Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, 3400 Civic Center, Boulevard, Room 11-101, Philadelphia, PA.
Kenneth B
KB
Margulies
Department of Pathology and Laboratory Medicine, UCLA Center for the Health Science, Room 13-145E, 10833 Le Conte Ave, Los Angeles, CA.
Haodong
H
Xu
Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD.
Xuejun
X
Wang
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.|Department of Laboratory Medicine and Pathology, University of Minnesota, Room 293, Dwan Variety Club Cardiovascular Research Center, 425 E River Pkwy, Minneapolis, MN.
Faqian
F
Li
D000328:Adult; D000818:Animals; D001665:Binding Sites; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003893:Desmin / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003893:Desmin; C000715470:MAS1 protein, human; C489427:MYC protein, human; C489428:Myc protein, mouse; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin
acetylation; cardiomyopathy; cell signaling/signal transduction; desmin; heart failure