NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells.

Leticia Batista Azevedo Rangel,Alice Laschuk Herlinger,Beihua Kong,Min Gao,Tian-Li Wang,Jin-Ming Yang,Ie-Ming Shih,Renchin Wu

doi:10.18632/aging.103203

Abstract

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.

Highlights

Nucleus accumbens-associated protein 1 (NAC1) is a transcriptional co-regulator that belongs to the bric-abrac tramtrack broad (BTB) family of proteins
Because NAC1 lacks the hallmark DNA binding motif of the BTB protein family, its capacity to modulate the expression of NAC1-target genes depends on interactions with other DNA-binding co-factors to form higher-order transcription complexes [1]
We found that the BCL6 consensus binding motif mapped to the promoters of several of these genes including FOXQ1, a gene directly regulated by NAC1

Summary

Introduction

Nucleus accumbens-associated protein 1 (NAC1) is a transcriptional co-regulator that belongs to the bric-abrac tramtrack broad (BTB) family of proteins. NAC1 mediates a plethora of biological functions [3,4,5,6] and has multifaceted roles in ovarian cancer pathogenesis and progression, including promotion of cell survival, proliferation and motility [2, 7,8,9], prevention of cell senescence [10], activation of autophagy [11], and acquisition of a chemoresistant phenotype [2, 8, 11,12,13]. NAC1 regulates the expression of over 700 genes in ovarian cancer, including FOXQ1, which is associated with increased mobility of tumor cells [19]. 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. 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. 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

Methods

Results

Conclusion