Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, PR China.
Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Aging (Albany NY). 2020 May 14;12(10):9275-9291. doi: 10.18632/aging.103203.
Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of "stem cell-like" phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors.
NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer.
The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy.
Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.
伏隔核相关蛋白 1（NAC1）在癌症的发病机制和进展中具有多方面的作用，包括耐药性的发展、细胞分裂的促进以及“干细胞样”表型的维持。NAC1 是一种转录共调节剂，属于 bric-a-brac tramtrack broad（BTB）蛋白家族，尽管它缺乏 BTB 家族的特征性 DNA 结合基序。高等转录复合物的形成可能依赖于其与其他 DNA 结合共因子的相互作用。
NAC1 通过其 C 端 BEN 结构域与 BCL6 相互作用，并形成一个复合物，该复合物结合启动子区域并激活 NAC1 靶基因 FOXQ1 的转录。NAC1 和 BCL6 协同上调。我们的分析还确定了 NAC1 在卵巢癌细胞中减弱 BCL6 自身下调的新功能。最后，我们发现肿瘤细胞中 NAC1 和 BCL6 调节的基因之间存在显著重叠，表明 NAC1 和 BCL6 协同控制癌症中的转录。
本研究的结果为 NAC1 的致癌作用提供了新的机制见解，并强调了开发针对 NAC1/BCL6 的癌症治疗的重要性。
使用 Cistrome 数据库和染色质免疫沉淀（ChIP）分析，我们确定了 BCL6 是 NAC1 的潜在相互作用分子。通过共免疫沉淀（Co-IP）、荧光素酶报告基因分析、免疫组织化学和微阵列分析，我们分析了 NAC1 和 BCL6 之间的相互作用以及它们调节下游基因（包括 FOXQ1）的机制。
