Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Key Laboratory for Experimental Teratology of the Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2021 Sep 28;36(13):109757. doi: 10.1016/j.celrep.2021.109757.
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.
乳腺癌干细胞（BCSCs）在肿瘤形成、耐药性、复发和转移中发挥重要作用。NANOG 是干细胞自我更新所必需的一种蛋白质，但它执行此功能的机制尚不清楚。在这里，我们表明缺氧诱导因子 1α（HIF-1α）是 NANOG 介导的 BCSC 富集所必需的。在机制上，NANOG 被 HIF-1 募集以协同激活编码端粒酶逆转录酶的 TERT 基因的转录，端粒酶逆转录酶维持端粒长度，这是干细胞自我更新所必需的。NANOG 通过募集去泛素化酶 USP9X 刺激 HIF-1 转录活性，USP9X 抑制 HIF-1α 蛋白降解，通过稳定 HIF-1α 与共激活因子 p300 的相互作用，介导组蛋白乙酰化。我们的结果描绘了 HIF-1 和 NANOG 介导 BCSC 自我更新的合作转录机制。
