Regulation of Cancer Stem Cell Self-Renewal by HOXB9 Antagonizes Endoplasmic Reticulum Stress-Induced Melanoma Cell Apoptosis via the miR-765–FOXA2 Axis

Abstract

Adaptation to endoplasmic reticulum (ER) stress has been indicated as a driver of malignancy and resistance to therapy in human melanoma. However, the relationship between cancer stem cells and adaptation to ER stress remains unclear. Here, we show that the ratio of cancer stem cells is increased in ER stress-resistant melanoma cells, which inhibit ER stress-induced apoptosis and promote tumorigenesis. Further mechanistic studies showed that HOXB9 triggered by ER stress favors cancer stem cell self-renewal and enhances ER stress resistance. HOXB9 directly binds to the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2, resulting in a FOXA2 decrease and cancer stem cell increase. Additionally, an increase in HOXB9 promotes melanoma growth and inhibits cell apoptosis in a mouse xenograft model. Elevated HOXB9 is found in human melanoma tissues, which is associated with microRNA-765 up-regulation and FOXA2 decreases. Thus, our data showed that the HOXB9-dependent, microRNA-765-mediated FOXA2 pathway contributes to the survival of melanoma under ER stress by maintaining the properties of cancer stem cells.