许多晚期人类癌症都存在瘤内缺氧区域，O2 梯度延伸至缺氧。缺氧诱导因子 (HIF) 在缺氧癌细胞中被激活，并驱动代谢重编程、血管化、侵袭和转移。缺氧通过诱导多能性因子 KLF4、NANOG、OCT4 和 SOX2 的表达和/或活性来诱导乳腺癌干细胞 (BCSC) 规范。最近的研究发现缺氧乳腺癌细胞中 PLXNB3、NARF 和 TERT 的 HIF-1 依赖性表达。 PLXNB3 结合并激活 MET 受体酪氨酸激酶，导致 SRC 非受体酪氨酸激酶激活，随后激活粘着斑激酶，从而促进癌细胞迁移和侵袭。 PLXNB3-MET-SRC 信号传导还会激活 STAT3，这是一种介导 NANOG 基因表达增加的转录因子。缺氧诱导的 NARF 与 OCT4 结合，并通过稳定 OCT4 与 KLF4、NANOG 和 SOX2 基因的结合以及稳定 OCT4 与 KDM6A 的相互作用来充当共激活剂，KDM6A 是一种组蛋白去甲基化酶，可消除组蛋白 H3 在赖氨酸 27 处的抑制性三甲基化，从而增加 KLF4、NANOG 和 SOX2 基因表达。除了通过这些机制增加多能因子表达外，HIF-1 还直接激活编码端粒酶的 TERT 基因的表达，端粒酶是维持端粒所需的酶，而端粒是 BCSC 无限自我更新所必需的。 HIF-1 与 TERT 基因结合并募集 NANOG，NANOG 通过促进随后募集 USP9X（一种抑制 HIF-1α 降解的去泛素酶）和 p300（一种介导 H3K27 乙酰化的组蛋白乙酰转移酶，这是转录激活。© 作者 2023。由牛津大学出版社出版。

Many advanced human cancers contain regions of intratumoral hypoxia, with O2 gradients extending to anoxia. Hypoxia-inducible factors (HIFs) are activated in hypoxic cancer cells and drive metabolic reprogramming, vascularization, invasion, and metastasis. Hypoxia induces breast cancer stem cell (BCSC) specification by inducing the expression and/or activity of the pluripotency factors KLF4, NANOG, OCT4, and SOX2. Recent studies have identified HIF-1-dependent expression of PLXNB3, NARF, and TERT in hypoxic breast cancer cells. PLXNB3 binds to and activates the MET receptor tyrosine kinase, leading to activation of the SRC non-receptor tyrosine kinase and subsequently focal adhesion kinase, which promotes cancer cell migration and invasion. PLXNB3-MET-SRC signaling also activates STAT3, a transcription factor that mediates increased NANOG gene expression. Hypoxia-induced NARF binds to OCT4 and serves as a coactivator by stabilizing OCT4 binding to the KLF4, NANOG, and SOX2 genes and by stabilizing the interaction of OCT4 with KDM6A, a histone demethylase that erases repressive trimethylation of histone H3 at lysine 27, thereby increasing KLF4, NANOG, and SOX2 gene expression. In addition to increasing pluripotency factor expression by these mechanisms, HIF-1 directly activates expression of the TERT gene encoding telomerase, the enzyme required for maintenance of telomeres, which is required for the unlimited self-renewal of BCSCs. HIF-1 binds to the TERT gene and recruits NANOG, which serves as a coactivator by promoting the subsequent recruitment of USP9X, a deubiquitinase that inhibits HIF-1α degradation, and p300, a histone acetyltransferase that mediates acetylation of H3K27, which is required for transcriptional activation.© The Author(s) 2023. Published by Oxford University Press.