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Published on: August 12, 2015
PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3
Ahmad Salameh1, Alessandro K Lee2, Marina Cardó-Vila3
1David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030;
Abstract:
Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.
Insights
Prostate cancer antigen 3 (PCA3) is a long noncoding RNA that regulates PRUNE2, a tumor suppressor. Their interaction offers a new target for prostate cancer diagnosis and therapy.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Prostate cancer antigen 3 (PCA3) is a specific biomarker for prostate cancer, but its function is unknown.
- Understanding PCA3's role is crucial for developing new diagnostic and therapeutic strategies.
Purpose of the Study:
- To elucidate the function of PCA3 and its regulatory mechanism in prostate cancer.
- To identify potential therapeutic targets based on the PCA3-PRUNE2 axis.
Main Methods:
- Identification of PRUNE2 as a target gene of PCA3.
- Investigation of the regulatory mechanism involving RNA editing by adenosine deaminase acting on RNA (ADAR).
- Assessment of the effects of PRUNE2 and PCA3 on cell proliferation and tumor growth in vitro and in vivo.
Main Results:
- PCA3 is classified as an antisense intronic long noncoding RNA (lncRNA) that regulates PRUNE2.
- A novel regulatory mechanism involving a PRUNE2/PCA3 double-stranded RNA and ADAR-dependent RNA editing was identified.
- PRUNE2 and PCA3 exhibited opposing effects on prostate cancer cell proliferation and tumor growth.
- Coregulation and RNA editing of PRUNE2 and PCA3 were validated in human prostate cancer specimens.
Conclusions:
- PCA3 functions as a dominant-negative oncogene, while PRUNE2 acts as a tumor suppressor in prostate cancer.
- The PRUNE2/PCA3 regulatory axis represents a significant molecular target for prostate cancer diagnostics and therapeutics.
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