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向BRPF3适度地逆转高度血清性卵巢癌中的olaparib耐药性

Benjamin G Bitler¹, Courtney A Bailey¹, Tomomi M Yamamoto¹

¹Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado School of Medicine, Aurora, Colorado, USA.

Molecular carcinogenesis

|July 26, 2023

概括

卵巢癌中对PARP抑制剂 (PARPi) 的耐药性是一个挑战. 向激素乙化,特别是H3K14ac,并没有改善PARPi反应,但抑制PCAF或BRPF3显示出克服PARPi耐药性的潜力.

科学领域:

在瘤学瘤学.
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
分子生物学分子生物学

背景情况:

PARP 抑制剂 (PARPi) 在治疗高度血清性卵巢癌 (HGSOC) 中至关重要.
在HGSOC治疗中,PARPi耐药性是一个重要的临床挑战.
基因组乙化,特别是H3K14ac和相关酶 (HAT) 参与DNA修复和复制.

研究的目的:

调查H3K14ac和相关HATs在PARPi耐药HGSOC中的表达和活性.
评估向H3K14ac或PARPi耐药HGSOC中的相关蛋白质的治疗潜力.

主要方法:

质谱测量以分析基因组修饰的情况.
逆转录酶定量PCR和RNA-seq用于分析基因表达.
基因淘汰和药理上抑制HATs和相关蛋白质 (PCAF,HBO1,BRPF3).

主要成果:

在耐PARPi的HGSOC细胞中观察到H3K14ac的丰富度增加.
在耐药细胞和患者衍生异种移植 (PDX) 模型中观察到HATs的改变表达.
镇压/抑制PCAF和BRPF3,但不是HBO1,调节的PARPi抵抗. H3K14ac的耗尽并没有影响PARPi的反应.

结论:

H3K14ac水平与HGSOC中的PARPi反应没有直接相关.
HATs (例如,PCAF) 或辅助蛋白 (例如,BRPF3) 的基功能可能比直接的HAT活动在调解PARPi反应方面更为关键.
针对PCAF或BRPF3是一个潜在的治疗策略,可以克服HGSOC中的PARPi抵抗.

关键词:

在 BRPF3 中,BRPF3 是在H3K14ac中使用.在HGSOC中,HGSOC是什么?这是一种PARP抑制剂.卵巢癌是发生在卵巢的癌症.电阻的电阻是指电阻的电阻

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