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Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10461-10466. doi: 10.1073/pnas.1706076114. Epub 2017 Sep 11.

Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF.

Author information

1
Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
2
Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan.
3
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
4
Department of Urology, Nihon University School of Medicine, Tokyo 173-0032, Japan.
5
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8652, Japan.
6
Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan; sinoue@tmig.or.jp.
7
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.

Abstract

Developing therapeutic approaches are necessary for treating hormone-refractory prostate cancer. Activation of androgen receptor (AR) and its variants' expression along with the downstream signals are mostly important for disease progression. However, the mechanism for marked increases of AR signals and its expression is still unclear. Here, we revealed that various spliceosome genes are aberrantly induced by RNA-binding protein PSF, leading to enhancement of the splicing activities for AR expression. Our high-speed sequence analyses identified global PSF-binding transcripts. PSF was shown to stabilize and activate key long noncoding RNAs and AR-regulated gene expressions in prostate cancer cells. Interestingly, mRNAs of spliceosome-related genes are putative primary targets of PSF. Their gene expressions are up-regulated by PSF in hormone-refractory prostate cancer. Moreover, PSF coordinated these spliceosome proteins to form a complex to promote AR splicing and expression. Thus, targeting PSF and its related pathways implicates the therapeutic possibility for hormone-refractory prostate cancer.

KEYWORDS:

NONO; PSF; RNA-binding protein; androgen receptor; prostate cancer

PMID:
28893982
PMCID:
PMC5625911
DOI:
10.1073/pnas.1706076114
[Indexed for MEDLINE]
Free PMC Article

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