Research Paper Volume 12, Issue 10 pp 9275—9291
NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells
- 1 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, PR China
- 2 Departments of Gynecology and Obstetrics, Oncology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
- 3 Biotechnology Program/Renorbio, Health Science Center, Federal University of Espírito Santo, Vitória, Brazil
- 4 Biochemistry and Pharmacology Program, Health Science Center, Federal University of Espírito Santo, Vitória, Brazil
- 5 Department of Pharmaceutical Sciences, Federal University of Espírito Santo, Vitória, Brazil
- 6 Department of Toxicology and Cancer Biology, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
- 7 Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Received: December 11, 2019 Accepted: March 9, 2020 Published: May 14, 2020https://doi.org/10.18632/aging.103203
How to Cite
Copyright © 2020 Gao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: 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.
Results: 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.
Conclusions: 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.
Methods: 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.