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PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation
Cell Reports ( IF 8.8 ) Pub Date : 2021-09-21 , DOI: 10.1016/j.celrep.2021.109747
Xiaorong Gu 1 , Francis Enane 2 , Rita Tohme 1 , Caroline Schuerger 1 , Tomas Radivoyevitch 3 , Yvonne Parker 1 , Eric Zuberi 4 , Bartlomiej Przychodzen 1 , Babal Kant Jha 1 , Daniel Lindner 1 , Brian Rini 5 , Yogen Saunthararajah 6
Affiliation  

PBRM1, a subunit of the PBAF coactivator complex that transcription factors use to activate target genes, is genetically inactivated in almost all clear cell renal cell cancers (RCCs). Using unbiased proteomic analyses, we find that PAX8, a master transcription factor driver of proximal tubule epithelial fates, recruits PBRM1/PBAF. Reverse analyses of the PAX8 interactome confirm recruitment specifically of PBRM1/PBAF and not functionally similar BAF. More conspicuous in the PAX8 hub in RCC cells, however, are corepressors, which functionally oppose coactivators. Accordingly, key PAX8 target genes are repressed in RCC versus normal kidneys, with the loss of histone lysine-27 acetylation, but intact lysine-4 trimethylation, activation marks. Re-introduction of PBRM1, or depletion of opposing corepressors using siRNA or drugs, redress coregulator imbalance and release RCC cells to terminal epithelial fates. These mechanisms thus explain RCC resemblance to the proximal tubule lineage but with suppression of the late-epithelial program that normally terminates lineage-precursor proliferation.



中文翻译:

肾癌中 PBRM1 的缺失使近端小管主转录因子中枢失衡以抑制近端小管分化

PBRM1 是 PBAF 共激活复合物的一个亚基,转录因子用于激活靶基因,它在几乎所有透明细胞肾细胞癌 (RCC) 中都被基因灭活。使用无偏蛋白质组学分析,我们发现 PAX8,近端小管上皮命运的主要转录因子驱动因子,招募 PBRM1/PBAF。PAX8 相互作用组的反向分析证实了专门招募 PBRM1/PBAF 而不是功能相似的 BAF。然而,在 RCC 细胞的 PAX8 中枢中更显眼的是辅助抑制因子,它在功能上与共激活因子相反。因此,与正常肾脏相比,RCC 中的关键 PAX8 靶基因受到抑制,组蛋白赖氨酸 27 乙酰化缺失,但赖氨酸 4 三甲基化激活标记完整。重新引入 PBRM1,或使用 siRNA 或药物消耗相反的辅助阻遏物,纠正共调节失衡并将 RCC 细胞释放到终末上皮细胞。因此,这些机制解释了 RCC 与近端小管谱系的相似性,但抑制了通常终止谱系前体增殖的晚期上皮程序。

更新日期:2021-09-21
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