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

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 1 alpha (HIF-1 alpha) 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-1 alpha protein degradation, and by stabilizing HIF-1 alpha 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.

Automated summary

NANOG and HIF-1 cooperatively activate the TERT gene to mediate breast cancer stem cell self-renewal, with NANOG stimulating HIF-1 transcriptional activity by recruiting USP9X and stabilizing the interaction between HIF-1 alpha and p300.