Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Indiana Center for Biomedical Innovation, Indiana University School of Medicine, Indianapolis, IN, USA.
Cell Rep. 2021 Sep 21;36(12):109747. doi: 10.1016/j.celrep.2021.109747.
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.
PBRM1 是 PBAF 共激活因子复合物的一个亚基，转录因子利用该复合物来激活靶基因，几乎所有的透明细胞肾细胞癌（RCC）中都存在 PBRM1 的基因失活。通过无偏蛋白组学分析，我们发现 PAX8，近端肾小管上皮命运的主要转录因子驱动因子，可招募 PBRM1/PBAF。对 PAX8 相互作用组的反向分析证实了 PBRM1/PBAF 的特异性招募，而不是功能相似的 BAF。然而，在 RCC 细胞中的 PAX8 枢纽中更明显的是核心抑制剂，其在功能上与共激活剂相反。因此，与正常肾脏相比，PAX8 的关键靶基因在 RCC 中受到抑制，组蛋白赖氨酸-27 乙酰化丢失，但赖氨酸-4 三甲基化激活标记保持完整。用 siRNA 或药物重新引入 PBRM1 或耗尽拮抗核心抑制剂，可纠正共调节剂失衡，使 RCC 细胞向终末上皮命运转变。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细胞增殖的晚期上皮程序。
