在骨髓瘤中向BRD4的应用和机制
Ding Chen1, Jiaming Tian2, Yihe Dong2
1Department of Orthopedic, Second Xiangya Hospital, Central South University, Changsha 410011, China. leocd23007@126.com.
概括
含基因的蛋白4 (BRD4) 通过O-GlcNAc修饰驱动骨髓瘤的进展和转移. 用 (+) -JQ1抑制BRD4抑制了瘤生长并改善了骨髓瘤模型中的存活率.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症生物学 癌症生物学
- 在瘤学瘤学.
背景情况:
- 转移是骨髓瘤死亡的主要原因,治疗选择有限.
- 一种表观遗传调节剂,含基因的蛋白4 (BRD4) 在各种癌症中显示出治疗潜力.
- 对于BRD4在骨髓瘤进展中的确切作用尚不清楚.
研究的目的:
- 研究BRD4在骨髓瘤进展中的分子机制.
- 探索BRD4抑制作为骨髓瘤的新疗法策略.
主要方法:
- 通过免疫光检测,评估了80个骨髓瘤组织中的BRD4表达.
- 使用卡普兰-梅尔分析 (GEO数据集GSE42352) 分析了88名患者的生存数据.
- 评估了BRD4抑制剂 (+) -JQ1在体内骨髓瘤模型和体内细胞试验 (MTT,殖民地形成,Transwell) 的疗效.
- 通过使用Co-IP/MS和Nano-LC MS/MS,确定了BRD4 O-GlcNAc修饰部位和相互作用基因.
主要成果:
- 在61.25%的骨髓瘤组织中,BRD4过度表达,与较短的存活率相关.
- (+) -JQ1在体内和体外显著抑制瘤生长,骨破坏,增殖,入侵和迁移.
- 在Thr73的BRD4 O-GlcNAc修饰对于蛋白质稳定性和EGFR氨酸激酶抑制剂抵抗路径的激活至关重要.
- (+) -JQ1治疗降低了EGFR和PDGFC等关键通路基因的调节,抑制了骨髓瘤恶性病变.
结论:
- 通过O-GlcNAc在Thr73.3的修饰,BRD4促进骨髓瘤的进展和转移.
- 抑制BRD4是一种有前途的骨髓瘤治疗策略.
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