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BAG3 epigenetically regulates GALNT10 expression via WDR5 and facilitates the stem cell-like properties of platin-resistant ovarian cancer cells
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2021-06-07 , DOI: 10.1016/j.bbamcr.2021.119077
Fu-Ying Zhao 1 , Qi Zhang 2 , Jia-Mei Wang 3 , Jing-Yi Jiang 1 , Ling-Yue Huyan 4 , Bao-Qin Liu 1 , Jing Yan 1 , Chao Li 1 , Hua-Qin Wang 1
Affiliation  

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.



中文翻译:

BAG3 通过 WDR5 在表观遗传学上调节 GALNT10 表达,并促进耐铂卵巢癌细胞的干细胞样特性

卵巢癌是最致命的妇科恶性肿瘤,通常由于其诊断晚和复发率高。来自不同恶性肿瘤(包括卵巢癌)的癌症干细胞 (CSC) 与化疗耐药和不良预后有关。因此,确定介导治疗耐药性的分子机制对于寻找治疗耐药性肿瘤的新靶点迫在眉睫。恶性转化过程中 GALNT 家族成员细微改变导致的异常 O-糖基化促进了各种癌症的转移。目前的研究表明,BAG3 在铂耐药的卵巢癌组织和细胞中上调,高 BAG3 预测卵巢癌患者的无病生存率很低。此外,目前的研究表明,BAG3 通过调节 GALTN10 促进了卵巢癌细胞的 CSC 样特性。在机制方面,BAG3 通过组蛋白 H3 赖氨酸 4 (H3K4) 呈递体 WDR5 表观遗传调节 GALNT10 反式激活。我们证明 WDR5 增加了 GALNT10 启动子区域的 H3K4 三甲基化 (H3K4me3) 修饰,促进了转录因子 ZBTB2 向 GALNT10 启动子的募集。总的来说,我们的研究揭示了 BAG3 通过 WDR5 对 GALNT10 的表观遗传上调,以促进抗铂卵巢癌的 CSC,为进一步鉴定对铂抗性卵巢癌具有治疗意义的有吸引力的靶标提供了额外的信息。BAG3 通过组蛋白 H3 赖氨酸 4 (H3K4) 呈递者 WDR5 表观遗传调节 GALNT10 反式激活。我们证明 WDR5 增加了 GALNT10 启动子区域的 H3K4 三甲基化 (H3K4me3) 修饰,促进了转录因子 ZBTB2 向 GALNT10 启动子的募集。总的来说,我们的研究揭示了 BAG3 通过 WDR5 对 GALNT10 的表观遗传上调,以促进抗铂卵巢癌的 CSC,为进一步鉴定对铂抗性卵巢癌具有治疗意义的有吸引力的靶标提供了额外的信息。BAG3 通过组蛋白 H3 赖氨酸 4 (H3K4) 呈递者 WDR5 表观遗传调节 GALNT10 反式激活。我们证明 WDR5 增加了 GALNT10 启动子区域的 H3K4 三甲基化 (H3K4me3) 修饰,促进了转录因子 ZBTB2 向 GALNT10 启动子的募集。总的来说,我们的研究揭示了 BAG3 通过 WDR5 对 GALNT10 的表观遗传上调,以促进抗铂卵巢癌的 CSC,为进一步鉴定对铂抗性卵巢癌具有治疗意义的有吸引力的靶标提供了额外的信息。

更新日期:2021-06-17
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