AC016745.3 Regulates the Transcription of AR Target Genes by Antagonizing NONO.

Yali Lu,Lu Zhang,Jun Luo,Wenhua Huang,Dujian Li,Yaoting Xu,Yan Huang,Xuechao Wan,Yao Li

doi:10.3390/life11111208

Yali Lu, Lu Zhang + Show 7 more

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https://doi.org/10.3390/life11111208

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Journal: Life	Publication Date: Nov 9, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Fudan University, Tongji University

Abstract

The androgen receptor (AR) and its related signaling pathways play an important role in the development of prostate cancer (PCa). Long non-coding RNAs (lncRNAs) are involved in the regulation of tumorigenesis and development, but their specific mechanism of action remains unclear. This study examines the function and mechanisms of action of lncRNA AC016745.3 in the development of PCa. It shows that dihydrotestosterone (DHT) results in the AR-dependent suppression of AC016745.3 expression in the LNCaP androgen-sensitive human prostate adenocarcinoma cell line. In addition, overexpression of AC016745.3 inhibits the proliferation and migration of PCa cells, and suppresses the expression of AR target genes. This research also demonstrates that the protein NONO interacts with AR and functions as an AR co-activator, promoting AR transcriptional activity. Furthermore, using RNA immunoprecipitation (RIP)-PCR experiments, the study demonstrates that both NONO and AR can bind AC016745.3. Moreover, cell phenotypic experiments reveal that NONO can promote cellular proliferation and migration, and that AC016745.3 can partially antagonize the pro-oncogenic functions of NONO in PCa cells. In summary, the results indicate that AC016745.3 can bind NONO, suppressing its ability to promote AR-dependent transcriptional activity. Furthermore, DHT-dependent suppression of AC016745.3 expression can enhance NONO’s promotion effect on AR.

Highlights

Prostate cancer (PCa) is a common malignancy of the male reproductive system
androgen receptor (AR) knockdown in LNCaP cells resulted in a significant upregulation in the expression of AC016745.3, whereas this had no such effect if the cells had previously been exposed to androgen deprivation treatment (Figure 1C,D)
Chromatin immunoprecipitation (ChIP)-PCR results revealed that the predicted AC016745.3 androgen response elements (AREs) sites were significantly enriched in AR immunoprecipitates, following the stimulation of LNCaP cells with 100 nM DHT (Figure 1F,G)

Summary

Introduction

Prostate cancer (PCa) is a common malignancy of the male reproductive system. The incidence of prostate cancer ranks second among male malignancies worldwide [1]. The androgen receptor (AR) and AR-related signaling pathways play important roles in the development of prostate cancer. PCa continues to produce PSA in large quantities [6,7], indicating that the AR signaling pathway remains intact as PCa cells transition to androgen independence [8]. Under such conditions, AR activity may be sustained via ligand-independent mechanisms. The role of AR and its downstream regulatory genes in the transition of the tumor to androgenindependence remains an area of intense interest in the field of PCa research

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