Abstract:
YWHAZ is elevated in many types of cancer including human breast cancer tissues, which closely correlated with clinicopathological features. YWHAZ promotes malignant progression in most of tumors. However, its involvement and molecular basis in ferroptosis are not clear. In this study, it was found that YWHAZ regulated ferroptosis in breast cancer. Inhibiting YWHAZ enhanced the sensitivity of breast cancer cells to RSL3 stimulated ferroptosis by increasing SLC7A11 expression. Ectopic YWHAZ expression suppressed RSL3 triggered ferroptosis by up-regulating SLC7A11 expression. In addition, it was also verified that YWHAZ involved in the above progress by HDAC2. YWHAZ suppression decreased SLC7A11 on transcriptional and protein levels. And Overexpression YWHAZ enhanced HDAC2, which increased SLC7A11 in breast cancer cells. YWHAZ inhibition enhanced ferroptosis by down-regulating SLC7A11 expression in cancer cells. Additionally, in vivo experiments showed that YWHAZ inhibition could increase the sensitivity of breast cancer xenografts to ferroptosis. Taken together, these findings identified the critical roles of YWHAZ in regulating ferroptosis sensitivity.
