mSWI/SNF家族子复合体的转移组合和功能是分离的子宫内膜癌中潜在的向依赖的基础
Jessica D St Laurent1,2,3, Grace D Xu1,2, Alexander W Ying1,2
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Nature genetics
|October 20, 2025
概括
在子宫内膜癌中,ARID1A/B亚单元的丧失会转移染色体重塑复合体,促进瘤生长. 抑制SMARCA4/SMARCA2 ATPases可以阻止癌细胞的增殖,并提高化疗的有效性.
科学领域:
- 分子生物学分子生物学
- 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.
背景情况:
- 哺乳动物SWI/SNF (mSWI/SNF) 复合体是调节基因表达的关键染色质重塑剂.
- 这些复合物存在不同的形式:正规的BRG1相关因子 (cBAF),多联BAF (PBAF) 和非正规的BAF (ncBAF).
- ARID1A和ARID1B子单元对于cBAF组合至关重要,并且经常发生突变,形成侵袭性的非分化/非分化子宫内膜癌 (DDEC/UECs).
研究的目的:
- 研究DDEC/UEC中ARID1A/B损失的功能后果.
- 探索在这些癌症中准mSWI/SNF ATPase子单元的治疗潜力.
主要方法:
- 利用细胞模型和人类原发性瘤样本.
- 评估了mSWI/SNF复合物的丰度和染色质的功能.
- 使用临床级的SMARCA4和/或SMARCA2 ATPase 抑制剂.
- 评估了瘤生长抑制和与卡博普拉丁化疗的协同作用.
主要成果:
- 缺少ARID1A/B导致cBAF损失,增加ncBAF和PBAF的丰度和功能.
- 这种转变维持了DDEC/UECs的致癌状态.
- 在体内,SMARCA4/SMARCA2 ATPase 抑制剂显著降低了DDEC细胞的增殖和瘤的生长.
- 抑制剂治疗与碳柏金协同作用,延长了生存时间.
结论:
- 由于ARID1A/B突变而导致的mSWI/SNF复合体静脉测量变化有助于DDEC/UEC瘤发生.
- 用小分子抑制剂向mSWI/SNF ATPase活性显示了对DDEC/UECs的治疗前景.
- 这种治疗策略也可能有利于其他具有cBAF破坏的癌症.
更多相关视频
08:33Combining Mitotic Cell Synchronization and High Resolution Confocal Microscopy to Study the Role of Multifunctional Cell Cycle Proteins During Mitosis
Published on: December 5, 2017
14.9K
06:54Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
14.2K
相关概念视频
Separation of Sister Chromatids
4.3K
At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
At the onset of anaphase, separase, a proteolytic enzyme, is...
4.3K
Cohesins
5.5K
Cohesin protein complexes are a molecular glue that holds two sister chromatids together. They play an important role both in mitosis and meiosis. In mitosis, all cohesin complexes present on the chromosomes are removed before the start of the anaphase stage.
Cohesin complexes in Meiotic Division
Meiosis involves two distinct rounds of chromosomal segregation and cell divisions— Meiosis I followed by Meiosis II – producing four daughter cells. Meiosis I includes the separation of...
Cohesin complexes in Meiotic Division
Meiosis involves two distinct rounds of chromosomal segregation and cell divisions— Meiosis I followed by Meiosis II – producing four daughter cells. Meiosis I includes the separation of...
5.5K
The Spindle Assembly Checkpoint
3.7K
The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
3.7K
Anaphase Promoting Complex
3.3K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
3.3K
