GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A.

Abstract

We previously demonstrated that expression of a Krüppel-like zinc finger transcription factor, GLIS1, dramatically increases under hypoxic conditions via a transcriptional mechanism induced by HIF-2α cooperating with AP-1 members. In this study, we focused on the functional roles of GLIS1 in breast cancer. To uncover its biological function, the effects of altered levels of GLIS1 in breast cancer cell lines on cellular growth, wound-healing and invasion capacities were assessed. Knockdown of GLIS1 using siRNA in BT-474 cells resulted in significant growth stimulation under normoxia, while attenuation was found in the cell invasion assay under hypoxic conditions. In MDA-MB-231 cells expressing exogenous 3xFLAG-tagged GLIS1, GLIS1 attenuated cell proliferation and enhanced cell mobility and invasion capacities under normoxia. In addition, breast cancer cells expressing GLIS1 acquired resistance to irradiation. Whole transcriptome analysis clearly demonstrated that downstream signals of GLIS1 are related to various cellular functions. Among the genes with increased expression, we focused on WNT5A. Knockdown of WNT5A indicated that enhancement of acquired cell motility in the MDA-MB-231 cells expressing GLIS1 was mediated, at least in part, by WNT5A. In an analysis of publicly available data, patients with estrogen receptor-negative breast cancer showing high levels of GLIS1 expression showed much worse prognosis than those with low levels. In summary, hypoxia-induced GLIS1 plays significant roles in breast cancer cells via regulation of gene expression related to cell migration and invasion capacities, resulting in poorer prognosis in patients with advanced breast cancer.

• Authors: Kazumi Shimamoto, Keiji Tanimoto, Takahiro Fukazawa, Hideaki Nakamura, Akinori Kanai, Hidemasa Bono, Hiromasa Ono, Hidetaka Eguchi, Nobuyuki Hirohashi
• Journal: Carcinogenesis (Carcinogenesis) Vol. 41 Issue 9 Pg. 1184-1194 (09 24 2020) ISSN: 1460-2180 [Electronic] England
• PMID: 32047936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Biomarkers, Tumor
• DNA-Binding Proteins
• GLIS1 protein, human
• Transcription Factors
• WNT5A protein, human
• Wnt-5a Protein

Topics

• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Invasiveness
• Prognosis
• Survival Rate
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Wnt-5a Protein (genetics, metabolism)