Dataset Information

Bach1 Represses Wnt/?-Catenin Signaling and Angiogenesis.

ABSTRACT: RATIONALE:Wnt/?-catenin signaling has an important role in the angiogenic activity of endothelial cells (ECs). Bach1 is a transcription factor and is expressed in ECs, but whether Bach1 regulates angiogenesis is unknown. OBJECTIVE:This study evaluated the role of Bach1 in angiogenesis and Wnt/?-catenin signaling. METHODS AND RESULTS:Hind-limb ischemia was surgically induced in Bach1(-/-) mice and their wild-type littermates and in C57BL/6J mice treated with adenoviruses coding for Bach1 or GFP. Lack of Bach1 expression was associated with significant increases in perfusion and vascular density and in the expression of proangiogenic cytokines in the ischemic hindlimb of mice, with enhancement of the angiogenic activity of ECs (eg, tube formation, migration, and proliferation). Bach1 overexpression impaired angiogenesis in mice with hind-limb ischemia and inhibited Wnt3a-stimulated angiogenic response and the expression of Wnt/?-catenin target genes, such as interleukin-8 and vascular endothelial growth factor, in human umbilical vein ECs. Interleukin-8 and vascular endothelial growth factor were responsible for the antiangiogenic response of Bach1. Immunoprecipitation and GST pull-down assessments indicated that Bach1 binds directly to TCF4 and reduces the interaction of ?-catenin with TCF4. Bach1 overexpression reduces the interaction between p300/CBP and ?-catenin, as well as ?-catenin acetylation, and chromatin immunoprecipitation experiments confirmed that Bach1 occupies the TCF4-binding site of the interleukin-8 promoter and recruits histone deacetylase 1 to the interleukin-8 promoter in human umbilical vein ECs. CONCLUSIONS:Bach1 suppresses angiogenesis after ischemic injury and impairs Wnt/?-catenin signaling by disrupting the interaction between ?-catenin and TCF4 and by recruiting histone deacetylase 1 to the promoter of TCF4-targeted genes.

SUBMITTER: Jiang L

PROVIDER: S-EPMC4676728 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis.

Jiang Li L Yin Meng M Wei Xiangxiang X Liu Junxu J Wang Xinhong X Niu Cong C Kang Xueling X Xu Jie J Zhou Zhongwei Z Sun Shaoyang S Wang Xu X Zheng Xiaojun X Duan Shengzhong S Yao Kang K Qian Ruizhe R Sun Ning N Chen Alex A Wang Rui R Zhang Jianyi J Chen Sifeng S Meng Dan D

Circulation research 20150629 4

<h4>Rationale</h4>Wnt/β-catenin signaling has an important role in the angiogenic activity of endothelial cells (ECs). Bach1 is a transcription factor and is expressed in ECs, but whether Bach1 regulates angiogenesis is unknown.<h4>Objective</h4>This study evaluated the role of Bach1 in angiogenesis and Wnt/β-catenin signaling.<h4>Methods and results</h4>Hind-limb ischemia was surgically induced in Bach1(-/-) mice and their wild-type littermates and in C57BL/6J mice treated with adenoviruses cod ...[more]

PMID: 26123998

Similar Datasets

Project description:Rationale: The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

Dataset Information

Bach1 Represses Wnt/?-Catenin Signaling and Angiogenesis.

Publications

Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets