Profiling of Androgen-Dependent Enhancer RNAs Expression in Human Prostate Tumors: Search for Malignancy Transition Markers

• Published in: Research and reports in urology 2021-01, Vol.13, p.705-713
• Main Authors: Nishimura, Koichi, Mori, Jinichi, Sawada, Takahiro, Nomura, Shuhei, Kouzmenko, Alexander, Yamashita, Kaori, Kanemoto, Yoshiaki, Kurokawa, Tomohiro, Hayakawa, Akira, Tokiwa, Suguru, Ochi, Michihisa, Shimmura, Hiroaki, Kato, Shigeaki
• Format: Article
• Language: English
• Subjects: androgen receptor; Androgen receptors; Androgens; Biopsy; Carcinogenesis; Chromatin; enhancer rna; Enhancers; epigenetic modification; Epigenetics; Gene expression; KLK3 gene; Laboratories; Malignancy; Molecular modelling; Non-coding RNA; Original Research; Patients; Prostate cancer; Prostate-specific antigen; Proteins; psa; Regression analysis; Regulatory sequences; Statistical analysis; Transcription; Tumorigenesis; Tumors
• ISSN: 2253-2447; 2253-2447
• DOI: 10.2147/RRU.S328661

Although the ability of androgens to promote prostate cancer development has been known for decades, the molecular mechanisms of androgen receptor (AR) signaling in the tumorigenesis remain unclear. Enhancer RNAs (eRNAs) transcribed from strong enhancers, or super-enhancers (SEs), have recently emerged as a novel class of regulatory non-coding RNAs (ncRNAs) that facilitate transcription, including that of androgen target genes, through chromatin looping to position enhancers proximate to the promoters. The aim of this study was to assess androgen-dependent transcription in prostate tumors of eRNAs (designated as KLK3eRNAs) from the SE of the gene encoding the prostate-specific antigen (PSA) protein, a clinical marker of prostate carcinogenesis. The androgen-induced KLK3eRNAs were identified in the LNCaP human prostate cancer cell line. The expressions of these KLK3eRNAs together with KLK3 and AR mRNA transcripts were assessed by qRT-PCR in prostate tumor samples from five prostate cancer patients. Androgen-induced KLK3eRNAs have been identified in the LNCaP cells, and their expression was further analyzed in tumors of prostate cancer patients. Transcripts of the tested KLK3eRNAs have been detected in all clinical samples, but their expression patterns differed between individual tumor specimens. We found a statistically significant correlation between the levels of the KLK3 and AR mRNAs with those of the previously reported KLK3eRNAs, while such correlation was not observed for novel KLK3eRNAs described in our recent report. Presented data suggest that prostate tumor development may associate with epigenetic reorganization in the KLK3 genomic regulatory elements reflected by changes of the KLK3eRNA expression. Our findings support a potential of eRNAs profiling to be used as diagnostic marker.