Perturbation of mammary epithelial cell apicobasal polarity by RHBDF1-facilitated nuclear translocation of PKCζ

• Published in: Biological research 2024-11, Vol.57 (1), p.90-11, Article 90
• Main Authors: Zhao, Huan-Yu, Zhu, Yi-Pan, Wen, Ying, Sun, Jing, Ding, Xin-Yu, Cao, Xin-Yu, Wu, Kai-Liang, Fu, Li, Li, Lu-Yuan
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - physiology; Adherens junction; Apicobasal polarity; Breast cancer; Breast carcinoma; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell culture; Cell invasion; Cell junctions; Cell Movement - physiology; Cell Nucleus - metabolism; Cell Polarity - physiology; Endoplasmic reticulum; Epithelial cells; Epithelial Cells - metabolism; Female; Humans; Investigations; Kinases; Mammary gland; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Molecular modelling; Morphogenesis; Nuclear transport; Phosphorylation; PKCζ; Polarity; Protein kinase C; Protein Kinase C - metabolism; Protein transport; Proteins; RHBDF1; Tight junction; Tumorigenesis
• ISSN: 0717-6287; 0716-9760; 0717-6287
• DOI: 10.1186/s40659-024-00566-2

The establishment of apicobasal polarity in epithelial cells is of critical importance in morphogenesis of mammary gland and other secretive gland tissues. The demise of the polarity is a critical step in early stages of tumorigenesis such as in breast ductal carcinoma in situ. The underlying molecular mechanism thus warrants in-depth investigations. Protein kinase C isoform ζ (PKCζ), which is highly expressed in breast cancer cells, accumulates in the nuclei of human mammary epithelial cells overexpressing human rhomboid family-1 (RHBDF1), an endoplasmic reticulum membrane protein. Nuclear translocation of PKCζ results in the failure of the formation of the cytosolic apicobasal polarity complex Par, of which PKCζ is an essential component. Additionally, enhanced nuclear translocation of PKCζ is accompanied by an inhibition of the expression of cell tight junction and adherens junction proteins and an increase of cell mobility. Mechanistically, RHBDF1 is able to interact with importin β1 and PKCζ and promote PKCζ phosphorylation. Consistently, treatment of RHBDF1-overexpressing cells with an inhibitor of PKCζ phosphorylation leads to restoration of apicobasal polarity and cell-cell junctions, as well as suppressed cell mobility. RHBDF1-facilitated nuclear translocation of PKCζ is critically responsible for the dismantlement of epithelial cell apicobasal polarity, and thus may serve as a target in the development of therapeutic approaches against early stages of breast cancer.