Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 39, Pages 10461-10466Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1706076114
Keywords
androgen receptor; RNA-binding protein; PSF; NONO; prostate cancer
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Funding
- Cell Innovation Program
- P-DIRECT
- P-CREATE from Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science, Japan [15K15581, 15K15353]
- National Institute of Biomedical Innovation, Japan
- Ministry of Health, Labor and Welfare, Japan
- Terumo Foundation for Life Sciences and Arts
- Princess Takamatsu Cancer Research Fund
- Uehara Memorial Foundation, Japan [201520122j]
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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 PSFbinding 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.
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