The FZD 7‐TWIST 1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma

The FZD 7‐TWIST 1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma
Title:
The FZD 7‐TWIST 1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma
Other Titles:
Molecular Oncology
Keywords:
Publication Date:
11 December 2018
Citation:
Tan, M., Asad, M., Heong, V., Wong, M.K., Tan, T.Z., Ye, J., Kuay, K.T., Thiery, J.P., Scott, C. and Huang, R.Y.‐J. (2019), The FZD 7‐TWIST 1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma. Mol Oncol, 13: 757-780. doi:10.1002/1878-0261.12425
Abstract:
Frizzled family receptor 7 (FZD 7 ), a Wnt signaling receptor, is associated with the maintenance of stem cell properties and cancer progression. FZD 7 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 FZD 7 and its functional roles. We found that FZD 7 expression was crucial to the maintenance of the mesenchymal phenotype, anoikis resistance, and spheroid and tumor formation in ovarian cancer (OC). We identified TWIST 1 as the crucial downstream effector of the FZD 7 pathway. TWIST 1 , a basic helix loop helix transcription factor, is known to associate with mesenchymal and cancer stem cell phenotypes. Manipulating TWIST 1 expression mimicked the functional consequences observed in the FZD 7 model, and overexpression of TWIST 1 partially rescued the functional phenotypes abolished by FZD 7 knockdown. We further proved that FZD 7 regulated TWIST 1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST 1 proximal promoter. We also identified that the FZD 7‐TWIST 1 axis regulates the expression of BCL 2 , a gene that controls apoptosis. Identification of this FZD 7‐TWIST 1‐BCL 2 pathway reaffirms the mechanism of anoikis resistance in OC. We subsequently showed that the FZD 7‐TWIST 1 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 FZD 7‐TWIST 1 axis is important for tumorigenesis and anoikis resistance, and therapeutic inhibition results in cell death in OCs.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative to Cancer Science Institute of Singapore to JPT and RYH, National Medical Research Council (NMRC) Clinician Scientist-Individual Research Grant (CS-IRG) (NMRC/CIRG/1449/2016) to RYH, and National University Cancer Institute Singapore (NCIS) Yong Siew Yoon (YSY) Research Grant through donations from the Yong Loo Lin Trust to JPT and RYH. CS was supported by fellowships and grants from the National Health and Medical Research Council (NHMRC Australia) Project grant 1081178, the Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research), and the Victorian Cancer Agency (Clinical Fellowships CRF 10-20, CRF16014).
Description:
ISSN:
1574-7891
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