ΔNp63标记并为TGFβ诱导的癌细胞干细胞和侵入性创造一个可访问的表观遗传环境
Eleftheria Vasilaki1,2, Yu Bai3, Mohamad Moustafa Ali3
1Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Uppsala, SE-751 23, Sweden. eleftheria.vasilaki@scilifelab.uu.se.
Cell communication and signaling : CCS
|August 23, 2024
概括
转化生长因子β (TGFβ) 信号稳定了ΔNp63,增强了DNA结合,通过改变染色质可访问性和基因转录,促进了癌细胞干细胞和侵入性.
科学领域:
- 癌症生物学 癌症生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 转录因子 转录因子
背景情况:
- p63是一种具有多种功能的转录因子.
- 转化生长因子β (TGFβ) 信号影响瘤的进展,干和入侵.
- 在癌症中TGFβ,p63和表观遗传修饰之间的相互作用仍然不清楚.
研究的目的:
- 研究TGFβ信号在调节p63活动中的作用.
- 阐明TGFβ和p63影响染色质可访问性和基因转录的机制.
- 了解这种相互作用对癌细胞干细胞和侵袭的影响.
主要方法:
- 用小分子抑制剂和RNA沉默来进行功能丧失分析.
- 进行球体形成试验,染色体免疫沉和mRNA表达试验.
- 采用质谱和共免疫沉来识别p63相互作用体.
主要成果:
- 刺激TGFβ增强了乳腺癌细胞干细胞的强度,这种强度因ΔNp63耗尽而降低.
- 通过p38 MAPK的TGFβ信号,酸化并稳定了ΔNp63,增加了其DNA结合.
- TGFβ调节了组织蛋白修饰 (H3K27ac/H3K27me3) 并将p300招募到染色质中,促进了可访问性和转录性,这种影响取决于ΔNp63.3.
结论:
- 通过p38 MAPK和SMAD通路传递TGFβ信号,酸化并将ΔNp63招募到特定的基因位置.
- 这种相互作用促进了染色质可访问性和与癌症干和侵袭相关的基因的转录.
- ΔNp63在招募像p300这样的基因组修饰酶方面发挥着至关重要的作用,调解TGFβ的表观遗传效应.
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