@article{c0d985d5b8314640a2ddb597f9355be9,
title = "HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells",
abstract = "Breast cancer stem cells (BCSCs) play essential roles in tumor formation, drug resistance, relapse, and metastasis. NANOG is a protein required for stem cell self-renewal, but the mechanisms by which it performs this function are poorly understood. Here, we show that hypoxia-inducible factor 1α (HIF-1α) is required for NANOG-mediated BCSC enrichment. Mechanistically, NANOG is recruited by HIF-1 to cooperatively activate transcription of the TERT gene encoding the telomerase reverse transcriptase that maintains telomere length, which is required for stem cell self-renewal. NANOG stimulates HIF-1 transcriptional activity by recruitment of the deubiquitinase USP9X, which inhibits HIF-1α protein degradation, and by stabilizing HIF-1α interaction with the coactivator p300, which mediates histone acetylation. Our results delineate a cooperative transcriptional mechanism by which HIF-1 and NANOG mediate BCSC self-renewal.",
keywords = "aldehyde dehydrogenase, hypoxia, mammosphere, pluripotency factor, proteasome, telomere, tumor-initiating cells, ubiquitination",
author = "Haiquan Lu and Yajing Lyu and Linh Tran and Jie Lan and Yangyiran Xie and Yongkang Yang and Murugan, {Naveena L.} and Wang, {Yueyang J.} and Semenza, {Gregg L.}",
note = "Funding Information: We thank Rachel Geisler and Samantha Garcia of Novus Biologicals for providing antibodies listed in the Key resources table and Dr. Pai-Sheng Chen (National Cheng Kung University, Taiwan) for providing HIF-1α deletion mutants. We are grateful to Dr. Mary Armanios (Johns Hopkins University) for advice regarding TCGA dataset acquisition. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. This work was supported by grants from the American Cancer Society ( RP-16-239-06-COUN ), the Armstrong Family Foundation , and the Cindy Rosencrans Foundation . Funding Information: We thank Rachel Geisler and Samantha Garcia of Novus Biologicals for providing antibodies listed in the Key resources table and Dr. Pai-Sheng Chen (National Cheng Kung University, Taiwan) for providing HIF-1? deletion mutants. We are grateful to Dr. Mary Armanios (Johns Hopkins University) for advice regarding TCGA dataset acquisition. G.L.S. is an American Cancer Society Research Professor and the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. This work was supported by grants from the American Cancer Society (RP-16-239-06-COUN), the Armstrong Family Foundation, and the Cindy Rosencrans Foundation. H.L. and G.L.S. designed the research study. H.L. Y.L. L.T. J.L. Y.X. N.L.M. and Y.J.W. conducted the experiments and acquired data. H.L. Y.L. Y.Y. and N.L.M. performed database analyses. H.L. L.T. and N.L.M. performed statistical analysis. Y.L. and Y.Y. helped to develop methods. H.L. and G.L.S. analyzed the data and wrote the manuscript. G.L.S. supervised the study. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "28",
doi = "10.1016/j.celrep.2021.109757",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}