PDF(Pubmed)
Abstract：
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.
摘要：
肺腺癌（LUAD）是全球癌症相关死亡的主要原因，但潜在的分子机制仍不清楚。转录因子（TF）特异性蛋白1（SP1）在各种癌症的发生发展中起着至关重要的作用，包括LUAD.最近的研究表明，主TF可以形成相分离的大分子缩合物，以促进超增强子（SE）组装和癌基因表达。在这项研究中,我们证明了SP1经历相分离，其DNA结合域中的锌指3对于该过程至关重要。通过使用针对SP1和H3K27ac的抗体，使用核酸酶（CUT和RUN）在靶标下裂解和释放，我们发现SP1富集和SE元素之间存在显著的相关性，确定G蛋白信号传导20（RGS20）基因的调节因子是SP1通过SE机制调节的最可能的靶标，并使用不同的方法验证了这一发现。SP1的致癌活性依赖于其相分离能力和RGS20基因激活,糖原合成酶激酶J4（GSK-J4）可以消除，去甲基酶抑制剂.一起,我们的发现提供了证据，表明SP1通过相分离和SE机制调节其靶癌基因表达，从而促进LUAD细胞进展。这项研究还揭示了通过干预SP1介导的SE形成来进行LUAD治疗的创新靶标。
