HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells

• Published in: Cell reports (Cambridge) Vol. 36; no. 13; p. 109757
• Main Authors: Lu, Haiquan, Lyu, Yajing, Tran, Linh, Lan, Jie, Xie, Yangyiran, Yang, Yongkang, Murugan, Naveena L., Wang, Yueyang J., Semenza, Gregg L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.09.2021; Elsevier
• Subjects: aldehyde dehydrogenase; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Hypoxia - physiology; Gene Expression Regulation, Neoplastic - genetics; Humans; hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; mammosphere; Nanog Homeobox Protein - metabolism; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - metabolism; pluripotency factor; proteasome; Telomerase - metabolism; telomere; tumor-initiating cells; ubiquitination; hypoxia; proteasome; aldehyde dehydrogenase; ubiquitination; pluripotency factor; telomere; tumor-initiating cells; mammosphere
• DOI: 10.1016/j.celrep.2021.109757
• ISSN: 2211-1247

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. [Display omitted] •HIF-1α is required for NANOG-mediated breast cancer stem cell self-renewal•NANOG regulates TERT expression and telomere length as a HIF-1 coactivator•NANOG recruits deubiquitinase USP9X and stabilizes HIF-1α protein•NANOG stabilizes HIF-1α interaction with the coactivator p300 Lu et al. find that NANOG is necessary but not sufficient for breast cancer stem cell maintenance. NANOG functions as a HIF-1 coactivator to induce TERT expression in hypoxic breast cancer stem cells. These findings suggest a mechanism in which HIF-1 and NANOG cooperatively mediate breast cancer stem cell self-renewal.