Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

Qin, Kevin; Yu, Michael; Fan, Jiaming; Wang, Hongwei; Zhao, Piao; Zhao, Guozhi; Zeng, Wei Zhang; Chen, Connie; Wang, Yonghui; Wang, Annie; Schwartz, Zander; Hong, Jeffrey; Song, Lili; Wagstaff, William; Haydon, Rex C.; Luu, Hue H.; Ho, Sherwin; Reid, Russell R.; He, Tong‐Chuan; Shi, Lewis L.

doi:10.1016/j.gendis.2023.01.030

Cited by 47 publications

(13 citation statements)

References 430 publications

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“…Our experiments indicated that overexpressing ZBED3 reinstates the tumor-suppressive effects observed upon NSUN5 knockdown in Huh7 and Hep 3B cells. Additionally, since GSEA revealed that NSUN5 plays a role in the Wnt signaling pathway, where ZBED3 serves as a crucial mediator, we assessed the expression levels of key signaling molecules, such as β-catenin, c-Myc, and AXIN1 [ 37 , 38 ]. Consequently, we observed a close association between NSUN5-associated tumorigenesis and the Wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

Gu,

Li,

Gao

et al. 2024

Oncogene

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Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer-related mortality worldwide. Nop2/Sun domain family member 5 (NSUN5), a conserved RNA 5-methylcytosine methyltransferase, is conventionally recognized as oncogenic. However, its role in HCC development remains unknown. In this study, we observed a remarkable upregulation of NSUN5 expression in both tumor tissues from patients with HCC, establishing a correlation with unfavorable clinical outcomes. NSUN5 knockdown and overexpression significantly inhibited and promoted HCC cell proliferation, respectively. Additionally, employing a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RIP-seq techniques, we identified zinc finger BED domain-containing protein 3 (ZBED3) as a novel downstream target of NSUN5. Additionally, we found that the overexpression of ZBED3 counteracted the tumor-suppressing effect of NSUN5 knockdown and simultaneously reversed the inhibition of the Wnt/β-catenin signaling pathway. In summary, we elucidated the oncogenic role of NSUN5 in HCC development and identified the ZBED3/Wnt/β-catenin signaling pathway as its downstream target. This study provides a novel therapeutic target for further development in HCC treatment.

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Section: Discussionmentioning

confidence: 99%

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

Gu,

Li,

Gao

et al. 2024

Oncogene

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“…In this respect, we may envision that additional regulatory factors beyond β-catenin and the GR combine with those to regulate PRNP gene expression. Potential candidates include SMADs, since they both interact with β-catenin [ 8 ] and the GR [ 53 ] and relay the action of TGFβ, itself known to induce the expression of PrP C [ 9 , 51 ]. Further exploration is required to obtain an integrated view of the complex regulation of the PRNP gene in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In the CMS4 subtype that is associated with dismal prognosis, two pathways, namely TGFβ [ 6 ] and YAP/TAZ [ 7 ], have gathered special interest. These pathways are well known to crosstalk with Wnt-β-catenin signaling [ 8 ], and, therefore, are good candidates for influencing the Wnt-β-catenin output. Recently, we documented that the cellular prion protein PrP C , encoded by the PRNP gene, is an upstream regulator of these two major pathways in CMS4 CRC [ 9 ], and that its targeting is a promising approach to treat CMS4 patients [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

Mouillet-Richard,

Gougelet,

Passet

et al. 2024

J Transl Med

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Background The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. Methods We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. Results In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. Conclusions An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

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“…Our present data extends these results and finds two FZD2 variants also modulate facial narrowing at the same stage of development. The 425C>T variant has significantly weaker ATF2 reporter activity via the JNK-PCP pathway (JNK is downstream of RAC)(Qin et al, 2024). The ATF2 reporter was specifically designed to read out JNK-dependent activation of transcription factor ATF2 (Ohkawara and Niehrs, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…However, the 1301G>T variant also inhibited facial narrowing without affecting the ATF2 reporter. The reason could be that the 1301G>T variant inhibits the second PCP pathway – RhoA-ROCK(Qin et al, 2024). It is necessary in future to connect the h FZD2 1301G>T variant directly to measures of ROCK activity.…”

Section: Discussionmentioning

confidence: 99%

Craniofacial studies in chicken embryos confirm the pathogenicity of Frizzled2 variants associated with Robinow syndrome

Tophkhane,

Fu,

Verheyen

et al. 2023

Preprint

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Robinow syndrome (RS) is a rare, genetically heterogeneous condition caused by mutations in seven WNT pathway genes. The clinical presentation includes craniofacial widening and jaw hypoplasia. Here we tested the functional impact of two missenseFZD2variants in the frontonasal mass in the chicken embryo, the area homologous to the affected region in RS. Viruses coding for wild-type or variant forms of FZD2 (code for P142L and G434V) inhibited beak ossification in vivo and certain bones failed to differentiate, possibly mediated by decreased levels ofCTNNB1and abnormal BMP signaling. In primary cultures, variants of FZD2, inhibited chondrogenesis, caused increased nuclear shuttling of β-catenin and increased expression of early mesenchyme marker, TWIST which precedes chondrocyte specification. To determine the impact of the variants on WNT pathways we used luciferase reporters. The G434V and P142L plasmids dominantly interfered with wtFZD2 in SuperTopflash canonical assays. The P142L variant repressed the activity of the ATF2 reporter in the presence of theRor2co-receptor. This is the first study to show that the missense variants inFZD2have functional defects and that the upper face skeletal defects in chickens recapitulate features of the jaw hypoplasia and flat profile of people with Robinow Syndrome.

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

Cited by 47 publications

References 430 publications

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

Craniofacial studies in chicken embryos confirm the pathogenicity of Frizzled2 variants associated with Robinow syndrome

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