由非正规的EZH2驱动的翻译增加,在酶胺耐药前列腺癌中产生了合成漏洞
Shankha S Chatterjee1,2, Juan F Linares1,2, Tania Cid-Diaz1,2
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Nature communications
|November 20, 2024
概括
通过向蛋白质激酶PKCλ/ι,克服了对割抵抗性前列腺癌 (CRPC) 的抵抗力. 丢失PKCλ/ι会诱导一种抗性程序,从而在CRPC中产生一个漏洞.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 割耐性前列腺癌 (CRPC) 的治疗耐药性是一个重大的临床挑战.
- 血统可塑性,特别是对神经内分泌表型的可塑性,允许CRPC细胞在治疗中存活下来.
- 驱动这种适应性抵抗的表观遗传机制在很大程度上是未知的.
研究的目的:
- 调查蛋白质激酶lambda/iota (PKCλ/ι) 在调节增强体同源2 (EZH2) 的作用及其对CRPC治疗耐药性的影响.
- 阐明表观遗传重编程的分子机制,以促进CRPC适应向治疗.
主要方法:
- 研究了PKCλ/ι对EZH2的酸化及其对EZH2蛋白酶体降解的影响.
- 在PKCλ/ι缺乏CRPC模型中分析了在恩扎拉胺治疗下EZH2的cystrome开关.
- 评估了翻译机器的转录激活和诱导转化生长因子β (TGFβ) 抵抗程序.
主要成果:
- 通过PKCλ/ι介导的EZH2酸化对于其蛋白质体降解及其在多抑制复合体2 (PRC2) 中的正规作用至关重要.
- 在恩扎胺治疗期间PKCλ/ι的丧失导致EZH2结合 (cistrome) 转移到非正规位点.
- 这种异常的EZH2定位触发了蛋白质合成的增加,并激活了TGFβ介导的抵抗程序.
结论:
- PKCλ/ι在维持EZH2功能和防止CRPC中的适应性抵抗方面发挥着至关重要的作用.
- 破坏PKCλ/ι功能会促进一种由血统可塑性驱动的阻力机制,涉及EZH2和TGFβ信号传递.
- 缺乏PKCλ/ι的CRPC表现出对蛋白质合成的依赖性增加,为治疗向提供了潜在的合成脆弱性.
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