Androgen Receptor-Activated Enhancers Simultaneously Regulate Oncogene TMPRSS2 and lncRNA PRCAT38 in Prostate Cancer.

Chen Chen,Chang Chang,Huang Huang,Liang Liang,Su Su,Tang Tang,Li Li,Xie Xie,Song Song,Guo Guo

doi:10.3390/cells8080864

Abstract

Prostate cancer is a common carcinoma in males, the development of which involves the androgen receptor (AR) as a key regulator. AR transactivation induces the high expression of androgen-regulated genes, including transmembrane protease serine 2 (TMPRSS2) and long noncoding RNA prostate cancer-associated transcript 38 (PRCAT38). PRCAT38 and TMPRSS2 are both located on chromosome 21, separated by a series of enhancers. PRCAT38 is a prostate-specific long noncoding RNA that is highly expressed in cancer tissue as compared to normal tissue. Here, we show chromatin looping by enhancers E1 and E2 with the promoters for PRCAT38 and TMPRSS2, indicating the co-regulation of PRCAT38 and TMPRSS2 by the same enhancers. The knockout of enhancer E1 or E2 simultaneously impaired the transcription of PRCAT38 and TMPRSS2 and inhibited cell growth and migration. Moreover, the loop formation and enhancer activity were mediated by AR/FOXA1 binding and the activity of acetyltransferase p300. Our findings demonstrate the utilization of shared enhancers in the joint regulation of two oncogenes in prostate cancer cells.

Highlights

Prostate cancer is the most common cancer in males worldwide
To explore strongly the oncogenic Long noncoding RNAs (lncRNAs) and their lineage association in prostate cancer, we searched for uncharacterized transcripts that were highly expressed in prostate cancer samples in the MiTranscriptome project [33]
The regulatory units as promoters and enhancers control their targets in a time- and space-dependent format, which is affected by the combined action of external stimuli and internal environment, exemplified by the activation of the hormonal transcription factor androgen receptor (AR)

Summary

Introduction

Prostate cancer is the most common cancer in males worldwide. It is driven by androgen, androgen deprivation therapy is effective for the first line of treatment [1]. The transmembrane protease serine 2 gene (TMPRSS2) is located on chromosome 21, 21q22.3, and encodes for a protein of 492 amino acids. It is expressed in prostatic epithelium, kidney, pancreas and colon tissues [6]. TMPRSS2 is an androgen-regulated gene that is overexpressed in prostate cancer tissue and is involved in cancer cell invasion and metastasis [7].

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