Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
118
Journal Issue
3
Pages
e2014408118
Date Issued
2021
Author(s)
Chang P.-H.
Chen M.-C.
Tsai Y.-P.
Tan G.Y.T.
Hsu P.-H.
Tsai Y.-F.
Yang M.-H.
Hwang-Verslues W.W.
Abstract
Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial?mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis. ? 2021 National Academy of Sciences. All rights reserved.
Subjects
Circulating tumor cells (CTCs) | breast cancer | metastasis | desmoglein2 (DSG2) | HIF1α
SDGs
Other Subjects
desmoglein 2; hypoxia inducible factor 1alpha; transcription factor EZH2; desmoglein 2; DSG2 protein, human; EZH2 protein, human; HIF1A protein, human; hypoxia inducible factor 1alpha; polycomb repressive complex 2; small interfering RNA; SUZ12 protein, human; transcription factor; transcription factor EZH2; tumor protein; animal experiment; animal model; animal tissue; Article; breast cancer; cancer patient; cancer prognosis; circulating tumor cell; controlled study; correlational study; down regulation; epithelial mesenchymal transition; female; gene; gene expression; human; human tissue; hypoxia; metastasis; mouse; nonhuman; prevalence; priority journal; protein expression; protein function; recurrence risk; tumor cell; tumor growth; animal; breast tumor; drug screening; gene expression regulation; genetics; lymph node metastasis; metabolism; mortality; pathology; promoter region; SCID mouse; signal transduction; survival analysis; tumor cell line; tumor embolism; tumor recurrence; tumor volume; Animals; Breast Neoplasms; Cell Line, Tumor; Desmoglein 2; Enhancer of Zeste Homolog 2 Protein; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphatic Metastasis; Mice; Mice, SCID; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Polycomb Repressive Complex 2; Promoter Regions, Genetic; RNA, Small Interfering; Signal Transduction; Survival Analysis; Transcription Factors; Tumor Burden; Xenograft Model Antitumor Assays
Publisher
National Academy of Sciences
Type
journal article