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Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer

Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 ac...

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Autores principales: Zhu, Huifang, Su, Zijie, Ning, Jiong, Zhou, Liang, Tan, Lifeng, Sayed, Sapna, Song, Jiaxing, Wang, Zhongyuan, Li, Huan, Sun, Qi, Liu, Shanshan, Sha, Ou, Leng, Feng, Chen, Xianxiong, Lu, Desheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494741/
https://www.ncbi.nlm.nih.gov/pubmed/34615853
http://dx.doi.org/10.1038/s41419-021-04211-8
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author Zhu, Huifang
Su, Zijie
Ning, Jiong
Zhou, Liang
Tan, Lifeng
Sayed, Sapna
Song, Jiaxing
Wang, Zhongyuan
Li, Huan
Sun, Qi
Liu, Shanshan
Sha, Ou
Leng, Feng
Chen, Xianxiong
Lu, Desheng
author_facet Zhu, Huifang
Su, Zijie
Ning, Jiong
Zhou, Liang
Tan, Lifeng
Sayed, Sapna
Song, Jiaxing
Wang, Zhongyuan
Li, Huan
Sun, Qi
Liu, Shanshan
Sha, Ou
Leng, Feng
Chen, Xianxiong
Lu, Desheng
author_sort Zhu, Huifang
collection PubMed
description Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 action on Wnt/β-catenin signaling is completely unclear. In the current study, TMEM97 was identified as an LRP6-interacting protein. TMEM97 could interact with LRP6 intracellular domain and enhance LRP6-mediated Wnt signaling in a CK1δ/ε-dependent manner. The binding of TMEM97 to LRP6 facilitated the recruitment of CK1δ/ε to LRP6 complex, resulting in LRP6 phosphorylation at Ser 1490 and the stabilization of β-catenin. In breast cancer cells, knockout of TMEM97 attenuated the Wnt/β-catenin signaling cascade via regulating LRP6 phosphorylation, leading to a decrease in the expression of Wnt target genes AXIN2, LEF1, and survivin. TMEM97 deficiency also suppressed cell viability, proliferation, colony formation, migration, invasion, and stemness properties in breast cancer cells. Importantly, TMEM97 knockout suppressed tumor growth through downregulating the Wnt/β-catenin signaling pathway in a breast cancer xenograft model. Taken together, our results revealed that TMEM97 is a positive modulator of canonical Wnt signaling. TMEM97-mediated Wnt signaling is implicated in the tumorigenesis of breast cancer, and its targeted inhibition may be a promising therapeutic strategy for breast cancer.
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spelling pubmed-84947412021-10-07 Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer Zhu, Huifang Su, Zijie Ning, Jiong Zhou, Liang Tan, Lifeng Sayed, Sapna Song, Jiaxing Wang, Zhongyuan Li, Huan Sun, Qi Liu, Shanshan Sha, Ou Leng, Feng Chen, Xianxiong Lu, Desheng Cell Death Dis Article Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 action on Wnt/β-catenin signaling is completely unclear. In the current study, TMEM97 was identified as an LRP6-interacting protein. TMEM97 could interact with LRP6 intracellular domain and enhance LRP6-mediated Wnt signaling in a CK1δ/ε-dependent manner. The binding of TMEM97 to LRP6 facilitated the recruitment of CK1δ/ε to LRP6 complex, resulting in LRP6 phosphorylation at Ser 1490 and the stabilization of β-catenin. In breast cancer cells, knockout of TMEM97 attenuated the Wnt/β-catenin signaling cascade via regulating LRP6 phosphorylation, leading to a decrease in the expression of Wnt target genes AXIN2, LEF1, and survivin. TMEM97 deficiency also suppressed cell viability, proliferation, colony formation, migration, invasion, and stemness properties in breast cancer cells. Importantly, TMEM97 knockout suppressed tumor growth through downregulating the Wnt/β-catenin signaling pathway in a breast cancer xenograft model. Taken together, our results revealed that TMEM97 is a positive modulator of canonical Wnt signaling. TMEM97-mediated Wnt signaling is implicated in the tumorigenesis of breast cancer, and its targeted inhibition may be a promising therapeutic strategy for breast cancer. Nature Publishing Group UK 2021-10-06 /pmc/articles/PMC8494741/ /pubmed/34615853 http://dx.doi.org/10.1038/s41419-021-04211-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhu, Huifang
Su, Zijie
Ning, Jiong
Zhou, Liang
Tan, Lifeng
Sayed, Sapna
Song, Jiaxing
Wang, Zhongyuan
Li, Huan
Sun, Qi
Liu, Shanshan
Sha, Ou
Leng, Feng
Chen, Xianxiong
Lu, Desheng
Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title_full Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title_fullStr Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title_full_unstemmed Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title_short Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer
title_sort transmembrane protein 97 exhibits oncogenic properties via enhancing lrp6-mediated wnt signaling in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494741/
https://www.ncbi.nlm.nih.gov/pubmed/34615853
http://dx.doi.org/10.1038/s41419-021-04211-8
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