Notch3 Transactivates Glycogen Synthase Kinase-3-Beta and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer Cells

Weiling Chen; Yongqu Zhang; Ronghui Li; Wenhe Huang; Xiaolong Wei; De Zeng; Yuanke Liang; Yunzhu Zeng; Min Chen; Lixin Zhang; Wenliang Gao; Yuanyuan Zhu; Yaochen Li; Guojun Zhang

doi:10.3390/cells11182872

Cells (Sep 2022)

Notch3 Transactivates Glycogen Synthase Kinase-3-Beta and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer Cells

Weiling Chen,
Yongqu Zhang,
Ronghui Li,
Wenhe Huang,
Xiaolong Wei,
De Zeng,
Yuanke Liang,
Yunzhu Zeng,
Min Chen,
Lixin Zhang,
Wenliang Gao,
Yuanyuan Zhu,
Yaochen Li,
Guojun Zhang

Affiliations

Weiling Chen: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Yongqu Zhang: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Ronghui Li: Department of Medical Oncology, Xiang’an Hospital of Xiamen University, No. 2000 Xiang’an East Road, Xiamen 361101, China
Wenhe Huang: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Xiaolong Wei: Department of Pathology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou 515041, China
De Zeng: Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou 515041, China
Yuanke Liang: Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Shantou 515041, China
Yunzhu Zeng: Department of Pathology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou 515041, China
Min Chen: Key Laboratory for Endocrine-Related Cancer Precision Medicine of Xiamen, No. 2000 Xiang’an East Road, Xiamen 361101, China
Lixin Zhang: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Wenliang Gao: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Yuanyuan Zhu: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China
Yaochen Li: Department of Central Lab, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou 515041, China
Guojun Zhang: Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China

DOI: https://doi.org/10.3390/cells11182872
Journal volume & issue: Vol. 11, no. 18
p. 2872

Abstract

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As a critical transformational process in the attributes of epithelial cells, epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion, metastasis, and resistance to treatment, which contributes to the ultimate death of some patients with breast cancer. Glycogen synthase kinase-3-beta (GSK3β) is thought to be an EMT suppressor that down-regulates the protein, snail, a zinc finger transcription inhibitor, and regulates E-cadherin expression and the Wnt signaling pathway. Our previous studies have shown that Notch3 also inhibits EMT in breast cancer. In mammary gland cells, GSK3β physically bound and phosphorylated the intracellular domain of two Notch paralogs: N1ICD was positively regulated, but N2ICD was negatively regulated; however, the relationship between Notch3, GSK3β, and EMT in breast cancer is still unclear and crosstalk between Notch3 and GSK3β has not been widely investigated. In this study, we revealed that Notch3 was an essential antagonist of EMT in breast cancer cells by transcriptionally upregulating GSK3β. In breast cancer, MCF-7 and MDA-MB-231 cell lines, the silencing of Notch3 reduced GSK3β expression, which is sufficient to induce EMT. Conversely, ectopic Notch3 expression re-activated GSK3β and E-cadherin. Mechanistically, Notch3 can bind to the GSK3β promoter directly and activate GSK3β transcription. In human breast cancer samples, Notch3 expression is positively associated with GSK3β (r = 0.416, p = 0.001); moreover, high expressions of Notch3 and GSK3β mRNA are correlated to better relapse-free survival in all breast cancer patients via analysis in “the Kaplan–Meier plotter” database. In summary, our preliminary results suggested that Notch3 might inhibit EMT by trans-activating GSK3β in breast cancer cells. The suppression of Notch3 expression may contribute to EMT by transcriptionally downregulating GSK3β in breast cancer.

Published in Cells

ISSN: 2073-4409 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General): Cytology
Website: https://www.mdpi.com/journal/cells

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