在晚期前列腺癌中通过DNA甲基化调节SPDEF表达
Mousa Vatanmakanian1,2, Joshua J Steffan3, Sweaty Koul2,4,5
1Department of Biochemistry & Molecular Biology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
Frontiers in endocrinology
|October 30, 2023
概括
DNA甲基化使前列腺癌中的SPDEF表达沉默,增加瘤进展和死亡率,特别是在非洲裔美国男性中. 逆转这种表观遗传沉默可能会提供新的治疗策略.
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:
- 前列腺癌 (PCa) 是男性癌症死亡的主要原因,转移性割耐药PCa (mCRPC) 特别致命.
- 非洲裔美国男性面临不成比例地更高的PCa死亡率.
- 前列腺特异性转录因子SPDEF在PCa中起作用,其通过DNA甲基化调节与疾病进展有关.
研究的目的:
- 调查SPDEF及其通过DNA甲基化调节在前列腺癌进展中的作用.
- 评估表观遗传重编程对SPDEF表达和癌细胞行为的影响.
- 探索DNA甲基转移酶 (DNMTs) 作为PCa.中的潜在治疗点.
主要方法:
- 使用5-aza-2'-deoxycytidine (5Aza-dC) 和siRNA介导的DNMT沉默进行表观遗传重编程.
- 功能性测试包括伤口愈合,博伊登-室入侵和MTT扩散测试.
- 通过qRT-PCR和免疫涂抹分析SPDEF和DNMT表达的分析;使用双硫酸盐测序进行DNA甲基化分析.
主要成果:
- 随着PCa的进展 (格里森等级),SPDEF表达减少,其促进物的DNA甲基化增加.
- 在PCa中,DNMT表达升高,与SPDEF水平相反相关.
- 在PCa细胞中降低SPDEF可减少迁移和入侵;5Aza-dC或DNMT沉默可部分恢复SPDEF并减少入侵性.
结论:
- SPDEF基因的高甲基化是PCa进展期间其沉默的关键机制.
- 失去SPDEF表达是一种潜在的可逆表观遗传事件,有助于癌细胞可塑性.
- DNMT活动代表了针对PCa进展和治疗耐药性的治疗脆弱性.
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