BAG3 epigenetically regulates GALNT10 expression via WDR5 and facilitates the stem cell-like properties of platin-resistant ovarian cancer cells.

Abstract

Ovarian cancer is the most lethal gynecologic malignant cancer, frequently due to its late diagnosis and high recurrence. Cancer stem cells (CSCs) from different malignancies including ovarian cancer have been linked to chemotherapy resistance and poor prognosis. Therefore, identifying the molecular mechanisms mediating therapy resistance is urgent to finding novel targets for therapy-resistant tumors. Aberrant O-glycosylation ascribed to subtle alteration of GALNT family members during malignant transformation facilitate metastasis in various cancers. The current study demonstrated that BAG3 was upregulated in platin-resistant ovarian cancer tissues and cells, and high BAG3 predicted dismal disease-free survival of patients with ovarian cancer. In addition, the current study showed that BAG3 facilitated CSC-like properties of ovarian cancer cells via regulation of GALTN10. In a term of mechanism, BAG3 epigenetically regulated GALNT10 transactivation via histone H3 lysine 4 (H3K4) presenter WDR5. We demonstrated that WDR5 increased H3K4 trimethylation (H3K4me3) modification at the promoter regions of GALNT10, facilitating recruitment of transcription factor ZBTB2 to the GALNT10 promoter. Collectively, our study uncovers an epigenetic upregulation of GALNT10 by BAG3 via WDR5 to facilitate CSCs of platin-resistant ovarian cancers, providing additional information for further identification of attractive targets with therapeutic significance in platin-resistant ovarian cancer.