The FZD7‐TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma
| Title: | The FZD7‐TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma |
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| Authors: | Ming Tan, Mohammad Asad, Valerie Heong, Meng Kang Wong, Tuan Zea Tan, Jieru Ye, Kuee Theng Kuay, Jean Paul Thiery, Clare Scott, Ruby Yun‐Ju Huang |
| Source: | Molecular Oncology, Vol 13, Iss 4, Pp 757-780 (2019) |
| Publisher Information: | Wiley, 2019. |
| Publication Year: | 2019 |
| Collection: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | anoikis, BCL2, FZD7, ovarian carcinoma, tumorigenesis, TWIST1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | Frizzled family receptor 7 (FZD7), a Wnt signaling receptor, is associated with the maintenance of stem cell properties and cancer progression. FZD7 has emerged as a potential therapeutic target because it is capable of transducing both canonical and noncanonical Wnt signals. In this study, we investigated the regulatory pathway downstream of FZD7 and its functional roles. We found that FZD7 expression was crucial to the maintenance of the mesenchymal phenotype, anoikis resistance, and spheroid and tumor formation in ovarian cancer (OC). We identified TWIST1 as the crucial downstream effector of the FZD7 pathway. TWIST1, a basic helix loop helix transcription factor, is known to associate with mesenchymal and cancer stem cell phenotypes. Manipulating TWIST1 expression mimicked the functional consequences observed in the FZD7 model, and overexpression of TWIST1 partially rescued the functional phenotypes abolished by FZD7 knockdown. We further proved that FZD7 regulated TWIST1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST1 proximal promoter. We also identified that the FZD7‐TWIST1 axis regulates the expression of BCL2, a gene that controls apoptosis. Identification of this FZD7‐TWIST1‐BCL2 pathway reaffirms the mechanism of anoikis resistance in OC. We subsequently showed that the FZD7‐TWIST1 axis can be targeted by using a small molecule inhibitor of porcupine, an enzyme essential for secretion and functional activation of Wnts. In conclusion, our results identified that the FZD7‐TWIST1 axis is important for tumorigenesis and anoikis resistance, and therapeutic inhibition results in cell death in OCs. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1878-0261 1574-7891 |
| Relation: | https://doaj.org/toc/1574-7891; https://doaj.org/toc/1878-0261 |
| DOI: | 10.1002/1878-0261.12425 |
| Access URL: | https://doaj.org/article/627ec59c33f042d7ac79b4f714ad778a |
| Accession Number: | edsdoj.627ec59c33f042d7ac79b4f714ad778a |
| Database: | Directory of Open Access Journals |
| ISSN: | 18780261 15747891 |
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| DOI: | 10.1002/1878-0261.12425 |
| Published in: | Molecular Oncology |
| Language: | English |