TY - JOUR TI - Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer AU - Chang, Po-Hao AU - Chen, Min-Che AU - Tsai, Ya-Ping AU - Tan, Grace Y. T. AU - Hsu, Pang-Hung AU - Jeng, Yung-Ming AU - Tsai, Yi-Fang AU - Yang, Muh-Hwa AU - Hwang-Verslues, Wendy W. T2 - Proceedings of the National Academy of Sciences AB - 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. Author Information Po-Hao Changa, Min-Che Chenb, Ya-Ping Tsaib, Grace Y. T. Tana, Pang-Hung Hsuc, Yung-Ming Jengd, Yi-Fang Tsaie, Muh-Hwa Yangf, and Wendy W. Hwang-Versluesa,1aGenomics Research Center, Academia Sinica, 115 Taipei, Taiwan;bAsclepiumm Taiwan Co., Ltd, 25160 New Taipei City, Taiwan;cDepartment of Bioscience and Biotechnology, National Taiwan Ocean University, 20224 Keelung City, Taiwan;dDepartment of Pathology, National Taiwan University Hospital, 100 Taipei, Taiwan;eDepartment of Surgery, Taipei-Veterans General Hospital, 112 Taipei City, Taiwan;fInstitute of Clinical Medicine, National Yang-Ming University, 112 Taipei, TaiwanEdited by Daniel A. Haber, Massachusetts General Hospital, Charlestown, MA, and approved December 15, 2020 (received for review July 9, 2020) Footnotes↵1To whom correspondence may be addressed. Email: wendyhv@gate.sinica.edu.tw.Author contributions: P.-H.C. and W.W.H.-V. designed research; P.-H.C., G.Y.T.T., and P.-H.H. performed research; M.-C.C., Y.-P.T., Y.-M.J., Y.-F.T., and M.-H.Y. contributed new reagents/analytic tools; P.-H.C., P.-H.H., and Y.-M.J. analyzed data; and P.-H.C. and W.W.H.-V. wrote the paper.Competing interest statement: P.-H.C. and M.-C.C. are coinventors on a DSG2 monoclonal antibody patent owned by Asclepiumm Taiwan Co., Ltd. M.-C.C. has equity ownership in and serves on the board of directors of Asclepiumm Taiwan Co., Ltd.This article is a PNAS Direct Submission.This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2014408118/-/DCSupplemental. DA - 2021/01/19/ PY - 2021 DO - 10.1073/pnas.2014408118 DP - www.pnas.org VL - 118 IS - 3 J2 - PNAS LA - en SN - 0027-8424, 1091-6490 UR - https://www.pnas.org/content/118/3/e2014408118 Y2 - 2021/01/14/18:18:37 KW - HIF1α KW - breast cancer KW - circulating tumor cells (CTCs) KW - desmoglein2 (DSG2) KW - metastasis ER -