Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

AbstractBoth the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling down-regulated the expressions of a Wnt reporter as well as many Wnt target genes. Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and β–catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.

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Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00480.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. G241-G249 ◽

Cited By ~ 18

Author(s):

Shuji Yamamoto ◽

Hiroshi Nakase ◽

Minoru Matsuura ◽

Yusuke Honzawa ◽

Kayoko Matsumura ◽

...

Keyword(s):

Heparan Sulfate ◽

Wnt Signaling ◽

Binding Affinity ◽

Target Genes ◽

Glycogen Synthase ◽

Critical Role ◽

Intestinal Epithelial ◽

Canonical Wnt Signaling ◽

Small Intestinal ◽

Canonical Wnt

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.

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Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1

Journal of Cell Science ◽

10.1242/jcs.251140 ◽

2020 ◽

pp. jcs.251140

Author(s):

Carlo D. Cristobal ◽

Qi Ye ◽

Juyeon Jo ◽

Xiaoyun Ding ◽

Chih-Yen Wang ◽

...

Keyword(s):

Wnt Signaling ◽

Actin Polymerization ◽

Critical Role ◽

Dependent Manner ◽

Canonical Wnt Signaling ◽

Downstream Signaling ◽

Receptor Complexes ◽

Spinal Cord Dorsal ◽

Canonical Wnt ◽

Chick Spinal Cord

Wnt signaling plays a critical role in development across species and is dysregulated in a host of human diseases. A key step in signal transduction is the formation of Wnt receptor signalosomes, where a large number of components translocate to the membrane, cluster together, and amplify downstream signaling. However, the molecular processes that coordinate these events remain poorly defined. Here, we show that Daam2 regulates canonical Wnt signaling via the PIP2-PIP5K axis through its association with Rac1. Clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K, and PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner. Importantly, the localization of Daam2 complexes and Daam2-mediated canonical Wnt signaling is dependent upon actin polymerization. These studies highlight novel roles for Rac1 and the actin cytoskeleton in the regulation of canonical Wnt signaling and define Daam2 as a key scaffolding hub that coordinates membrane translocation and signalosome clustering. Key words: Daam2, Rac1, PIP5K, Wnt signalosome, chick spinal cord, dorsal patterning

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Faculty Opinions recommendation of Canonical Wnt signaling dynamically controls multiple stem cell fate decisions during vertebrate body formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13491958.15195056 ◽

2012 ◽

Author(s):

Virginia Papaioannou

Keyword(s):

Stem Cell ◽

Wnt Signaling ◽

Cell Fate ◽

Canonical Wnt Signaling ◽

Stem Cell Fate ◽

Body Formation ◽

Cell Fate Decisions ◽

Canonical Wnt

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Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade

Stem Cell Research & Therapy ◽

10.1186/scrt176 ◽

2013 ◽

Vol 4 (2) ◽

Cited By ~ 67

Author(s):

Luca Vanella ◽

Komal Sodhi ◽

Dong Hyun Kim ◽

Nitin Puri ◽

Mani Maheshwari ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Wnt Signaling ◽

Heme Oxygenase ◽

Lipid Accumulation ◽

Signaling Cascade ◽

Heme Oxygenase 1 ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015592 ◽

2020 ◽

Vol 295 (51) ◽

pp. 17560-17572

Author(s):

Siu Chiu Chan ◽

Sachin S. Hajarnis ◽

Sophia M. Vrba ◽

Vishal Patel ◽

Peter Igarashi

Keyword(s):

Wnt Signaling ◽

Transcriptional Repression ◽

Target Genes ◽

Regulatory Elements ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Canonical Wnt Signaling ◽

H3k27 Trimethylation ◽

Binding Factor ◽

Canonical Wnt

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

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Both Canonical and Non-Canonical Wnt Signaling Independently Promote Stem Cell Growth in Mammospheres

PLoS ONE ◽

10.1371/journal.pone.0101800 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101800 ◽

Cited By ~ 27

Author(s):

Alexander M. Many ◽

Anthony M. C. Brown

Keyword(s):

Stem Cell ◽

Cell Growth ◽

Wnt Signaling ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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The Microphthalmia-Associated Transcription Factor Mitf Interacts with β-Catenin To Determine Target Gene Expression

Molecular and Cellular Biology ◽

10.1128/mcb.02299-05 ◽

2006 ◽

Vol 26 (23) ◽

pp. 8914-8927 ◽

Cited By ~ 108

Author(s):

Alexander Schepsky ◽

Katja Bruser ◽

Gunnar J. Gunnarsson ◽

Jane Goodall ◽

Jón H. Hallsson ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Wnt Signaling ◽

Signaling Pathway ◽

Critical Role ◽

Wnt Signaling Pathway ◽

Feedback Mechanism ◽

Canonical Wnt Signaling ◽

Melanocyte Stem Cells ◽

Canonical Wnt

ABSTRACT Commitment to the melanocyte lineage is characterized by the onset of expression of the microphthalmia-associated transcription factor (Mitf). This transcription factor plays a fundamental role in melanocyte development and maintenance and seems to be crucial for the survival of malignant melanocytes. Furthermore, Mitf has been shown to be involved in cell cycle regulation and to play important functions in self-renewal and maintenance of melanocyte stem cells. Although little is known about how Mitf regulates these various processes, one possibility is that Mitf interacts with other regulators. Here we show that Mitf can interact directly with β-catenin, the key mediator of the canonical Wnt signaling pathway. The Wnt signaling pathway plays a critical role in melanocyte development and is intimately involved in triggering melanocyte stem cell proliferation. Significantly, constitutive activation of this pathway is a feature of a number of cancers including malignant melanoma. Here we show that Mitf can redirect β-catenin transcriptional activity away from canonical Wnt signaling-regulated genes toward Mitf-specific target promoters to activate transcription. Thus, by a feedback mechanism, Mitf can diversify the output of canonical Wnt signaling to enhance the repertoire of genes regulated by β-catenin. Our results reveal a novel mechanism by which Wnt signaling and β-catenin activate gene expression, with significant implications for our understanding of both melanocyte development and melanoma.

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Wnt3a nonredundantly controls hematopoietic stem cell function and its deficiency results in complete absence of canonical Wnt signaling

Blood ◽

10.1182/blood-2010-04-282624 ◽

2010 ◽

Vol 116 (3) ◽

pp. 496-497 ◽

Cited By ~ 29

Author(s):

Tiago C. Luis ◽

Brigitta A. E. Naber ◽

Willem E. Fibbe ◽

Jacques J. M. van Dongen ◽

Frank J. T. Staal

Keyword(s):

Stem Cell ◽

Wnt Signaling ◽

Hematopoietic Stem Cell ◽

Cell Function ◽

Canonical Wnt Signaling ◽

Hematopoietic Stem ◽

Canonical Wnt

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Downregulation of Cancer Stemness by Novel Diterpenoid Ovatodiolide Inhibits Hepatic Cancer Stem Cell-Like Traits by Repressing Wnt/β-Catenin Signaling

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500477 ◽

2018 ◽

Vol 46 (04) ◽

pp. 891-910 ◽

Cited By ~ 5

Author(s):

Mingche Liu ◽

Oluwaseun Adebayo Bamodu ◽

Kuang-Tai Kuo ◽

Wei-Hwa Lee ◽

Yen-Kuang Lin ◽

...

Keyword(s):

Stem Cell ◽

Wnt Signaling ◽

Signaling Pathway ◽

Anticancer Agents ◽

Target Therapy ◽

Wnt Signaling Pathway ◽

Tumor Evolution ◽

Canonical Wnt Signaling ◽

Differentiation Potential ◽

Canonical Wnt

The hierarchical tumor propagation or cancer stem cells (CSCs) model of carcinogenesis postulates that like physiologic adult stem cell (ASC), the CSCs positioned at the apex of any tumor population form the crux of tumor evolution with a constitutive regenerative capacity and differentiation potential. The propagation and recurrence of the characteristically heterogeneous and therapy-resistant hepatocellular carcinoma (HCC), adds to accumulating evidence to support this CSCs model. Based on the multi-etiologic basis of HCC formation which among others, focuses on the disruption of the canonical Wnt signaling pathway, this study evaluated the role of cembrane-type phytochemical, Ovatodiolide, in the modulation of the Wnt/[Formula: see text]-catenin pathway, and its subsequent effect on liver CSCs’ activities. Our fluorescence-activated cell sorting (FACS) and quantitative RT-PCR analyses of side population (SP) indicated that CD133+ cells were [Formula: see text]-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to [Formula: see text]-catenin-downregulated group. We demonstrated that marked upregulation of [Formula: see text]-catenin and its downstream targets effectively enhanced hepatosphere formation, with an associated induction of CD133, OCT4 and Sox2 expression and also caused an significant enhancement of HCC proliferation. However, treatment with Ovatodiolide induced downregulation of [Formula: see text]-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the [Formula: see text]-catenin-associated enhancement of HCC growth. In summary, we demonstrated for the first time that Ovatodiolide suppressed the canonical Wnt signaling pathway, and inhibited the generation of liver CSCs; Thus, projecting Ovatodiolide as a putatively effective therapeutic agent for anti-HCC target therapy.

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