CHD1的遗传损失调节了割抵抗性前列腺癌的发展中的独特的基因素翻译后修饰
Tanaya A Purohit1, Joseph Gawdzik2, Eric A Armstrong3
1Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA; Cancer Biology Program, University of Wisconsin, Madison, WI 53706, USA.
概括
染色体重塑剂CHD1的缺陷通过改变基因素修饰和降低关键酶的调节,驱动割抵抗性前列腺癌. 这种表观遗传状态赋予了针对NSD2.2的治疗方法的耐药性.
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:
- 在前列腺癌 (PC) 进展到割抵抗 (CR) 中,表观遗传改变至关重要.
- 驱动这些表观遗传变化的精确机制尚不清楚.
研究的目的:
- 为了研究前列腺癌割抵抗期间表观遗传景观的变化.
- 确定参与CRPC发育和治疗耐药性的新型分子参与者和机制.
主要方法:
- 激素后翻译修饰 (PTMs) 在激素敏感 (HS) 和割抵抗 (CR) 患者衍生的异种移植中进行分析.
- 在CRPC细胞系中CHD1淘汰 (KO),基因表达分析和机制研究.
- 大量RNA测序和ChIP-qPCR分析.
主要成果:
- 在CRPC中发现了一种新的染色质状态,具有CHD1缺乏和减少的H3.3K27/K36甲基化.
- 缺少CHD1导致基因组修饰酶NSD2和EZH2.2的表达和活性下降.
- 缺少CHD1降低了干扰素信号的调节,并赋予了对NSD2抑制的抵抗力.
结论:
- CHD1在维持表观遗传调节和抑制瘤抵抗方面发挥着至关重要的作用.
- CHD1调节基因组修饰酶,影响CRPC的血统可塑性和治疗脆弱性.
- 针对CHD1特异性的表观遗传脆弱性,为前列腺癌的新型个性化疗法提供了潜力.
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