染色体可访问性和先驱因子FOXA1限制了前列腺癌中葡萄糖皮质体受体的作用
Laura Helminen1, Jasmin Huttunen1, Melina Tulonen1
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Nucleic acids research
|November 28, 2023
概括
葡萄糖皮质体受体 (GR) 可以替代前列腺癌中的雄激素受体 (AR),从而导致抗雄激素疗法的耐药性. 我们发现FOXA1抑制GR,并抑制p300阻断GR活动,提供新的治疗策略.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 基因组学就是基因组学.
背景情况:
- 前列腺癌治疗通常涉及受体 (AR) 信号抑制.
- 癌细胞可以对抗雄激素疗法产生抗性.
- 葡萄糖皮质体受体 (GR) 可以通过替代AR功能来调解耐药性,但机制尚不清楚.
研究的目的:
- 阐明前列腺癌中GR介导的抗雄激素耐药性的机制.
- 在此背景下,确定GR行动的关键监管者.
主要方法:
- 用全基因组技术研究前列腺癌细胞中的GR作用.
- 对染色质可访问性和转录因子占用率 (FOXA1) 的分析.
- 基因沉默 (FOXA1) 和小分子抑制 (p300联合激活剂).
主要成果:
- 在耐药细胞中,GR取代AR在经FOXA1标记的预先可访问的染色质位点.
- 沉默FOXA1增强了GR染色体的结合和活性.
- 通过TLE3核心压缩器,FOXA1抑制NR3C1 (GR基因) 的表达.
- 抑制p300的酶活性阻断了GR介导的基因调节和增殖.
结论:
- 染色质预可及性和FOXA1介导的抑制是前列腺癌中GR作用的关键调节者.
- 这些发现揭示了克服类固醇受体介导的抗雄激素抵抗的新策略.
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