Trimethylation and Acetylation of β-Catenin at Lysine 49 Represent Key Elements in ESC Pluripotency

Hoffmeyer, Katrin; Junghans, Dirk; Kanzler, Benoı̂t; Kemler, Rolf

doi:10.1016/j.celrep.2017.02.076

Cited by 45 publications

(47 citation statements)

References 26 publications

(29 reference statements)

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“…We provide compelling mechanistic evidence that both HMGA2 and EZH2 are necessary for the maintenance of K49 acetylation of b-catenin mediated by CBP (27). The Wnt nuclear complex composed of b-CATENIN/TCF-4/LEF-1 (29) is necessary for Wnt-direct target gene expression, but was only maintained in the presence of both HMGA2 and EZH2.…”

Section: Discussionmentioning

confidence: 88%

“…The acetylation of lysine 49 (K49Ac) of bÀCATENIN, mediated by CBP, can be substituted by trimethylation (beta-catMe3) on K49 by EZH2 in embryonic stem cells, causing b-CATENIN to function as a transcriptional corepressor (27). We hypothesized that in the absence of either HMGA2 and/or EZH2, the K49Ac on ABC mediated by CBP would be lost.…”

Section: Loss Of a Single Hmga2 Allele Decreases Ezh2 Protein Expressmentioning

confidence: 99%

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The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Ayachi

Fatima

Wend³

et al. 2019

Cancer Research

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Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for b-CATE-NIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10b LacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for b-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on b-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC. Significance: These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.

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Section: Discussionmentioning

confidence: 88%

Section: Loss Of a Single Hmga2 Allele Decreases Ezh2 Protein Expressmentioning

confidence: 99%

The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Ayachi

Fatima

Wend³

et al. 2019

Cancer Research

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“…Alternatively, β‐catenin protein can sequester retinoic acid receptor preventing the promotion of Sox9 mRNA transcription (Weston, Chandraratna, Torchia, & Underhill, ; Yasuhara et al, ). Most recently, methylated form of β‐catenin (Me‐β‐catenin) was shown to function as a transcriptional repressor, leaving open the possibility that Me‐β‐catenin can repress Sox9 transcription (Hoffmeyer, Junghans, Kanzler, & Kemler, ). Chromatin occupancy of Me‐β‐catenin and functional analysis of regulatory elements should reveal its direct role in transcriptional inhibition of Sox9 .…”

Section: Signaling Factors Regulating the Calvarial Bone Initiation Pmentioning

confidence: 99%

A tale of two cities: The genetic mechanisms governing calvarial bone development

Ferguson

Atit

2018

Genesis

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The skull bones must grow in a coordinated, three-dimensional manner to coalesce and form the head and face. Mammalian skull bones have a dual embryonic origin from cranial neural crest cells (CNCC) and paraxial mesoderm (PM) and ossify through intramembranous ossification. The calvarial bones, the bones of the cranium which cover the brain, are derived from the supraorbital arch (SOA) region mesenchyme. The SOA is the site of frontal and parietal bone morphogenesis and primary center of ossification. The objective of this review is to frame our current in vivo understanding of the morphogenesis of the calvarial bones and the gene networks regulating calvarial bone initiation in the SOA mesenchyme.

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“…Thus, the downregulation of nuclear β -catenin and Wnt targets observed in spite of Chir-treatment suggests that events downstream of β -catenin stabilization in the cytoplasm are dynamically regulated in PSM cells differentiating in vitro. One such candidate is K49 β -catenin acetylation, which acts as a switch controlling mesodermal vs neural gene activation in mouse embryonic stem cells (22). To test whether K49 β -catenin acetylation is associated with the peak of Wnt activation in vitro, we used an antibody which specifically detects K49 acetyl β -catenin.…”

Section: Main Textmentioning

confidence: 99%

Intracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryo

Oginuma

Harima

Xiong

et al. 2018

Preprint

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Formation of the body of vertebrate embryos proceeds sequentially by posterior addition of tissues. While this process depends on aerobic glycolysis acting upstream of Wnt signaling in tail bud cells, the molecular details of this regulation are unknown. Here we used chicken embryos and human tail bud-like cells differentiated in vitro from iPS cells to show that glycolysis acts by increasing the intracellular pH (pHi) of tail bud cells. This promotesβ-catenin acetylation leading to Wnt signaling activation and the choice of a mesodermal fate at the expense of the neural fate in tail bud precursors. Our data suggest that by increasing the pHi of tail bud cells, aerobic glycolysis creates a favorable chemical environment for non-enzymatic acetylation of β-catenin, ultimately triggering Wnt signaling. AUTHOR CONTRIBUTIONS M.O. designed, performed and analyzed the chicken embryo experiments and the in vitro acetylation study of purified beta-catenin with O.P.; Y. H. designed, performed and analyzed the human iPS experiments with O.P.; F.X. performed the quantitative analysis of pHi in vivo. O.P. wrote the manuscript and supervised the project. All authors discussed and agreed on the results and commented on the manuscript.

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Trimethylation and Acetylation of β-Catenin at Lysine 49 Represent Key Elements in ESC Pluripotency

Cited by 45 publications

References 26 publications

The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

A tale of two cities: The genetic mechanisms governing calvarial bone development

Intracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryo

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