1. Medicine

Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts

  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap  Is a corresponding author
  1. University of New Mexico, United States
  2. University of Utah, United States
  3. Rutgers, The State University of New Jersey, United States
  4. University of São Paulo, Brazil
  5. University of Arkansas for Medical Sciences, United States
  6. University of Florida, United States
  7. Baylor College of Medicine, United States
  8. University of São Paulo, Brazil
  9. AC Camargo Cancer Center, Brazil
  10. A.C. Camargo Cancer Center, Brazil
  11. MBrace Therapeutics, United States
  12. University of California, San Diego, United States
  13. Rutgers Cancer Institute of New Jersey, United States
https://doi.org/10.7554/eLife.81929
Share this article
Cite this article
  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap
(2023)
Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
eLife 12:e81929.
https://doi.org/10.7554/eLife.81929
  2. Download BibTeX
  3. Download .RIS

Abstract

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.

Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically-annotated cases post-radical prostatectomy: a single-institution discovery cohort (n=107) and a multi-institution validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.

Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages.

Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted.

Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Data availability

For the discovery cohort, all data generated or analyzed are included in the manuscript and source data files, except for patient-level ethnicity data. Patient-level ethnicity data is not included due to the potential for identifiability. However detailed summary ethnicity data is presented in the manuscript and in Table 1. Requests to access the patient level ethnicity data should be directed to the corresponding author with a project proposal. Source codes are also available in the supplemental source code file. For the Validation Cohort, clinicopathological patient characteristics and gene level transcription data from The Cancer Genome Atlas (TCGA) were accessed from the UCSC Xena Resource.

The following previously published data sets were used

Article and author information

Author details

  1. Richard C Lauer

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  2. Marc Barry

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.

  3. Tracey L Smith

    Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    No competing interests declared.

  4. Andrew Maltez Thomas

    Department of Biochemistry, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5789-3354

  5. Jin Wu

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  6. Ruofei Du

    Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, United States
    Competing interests
    No competing interests declared.

  7. Ji-Hyun Lee

    Department of Biostatistics, University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6420-5150

  8. Arpit Rao

    Department of Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  9. Andrey S Dobroff

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  10. Marco A Arap

    Division of Urology, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.

  11. Diana N Nunes

    Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil
    Competing interests
    Diana N Nunes, The University of New Mexico filed patent applications on PRUNE2- related technology, for which Diana Nunes was an inventor (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. No payments were made to Diana Nunes, and the author has no other competing interests to declare..

  12. Israel T Silva

    Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil
    Competing interests
    No competing interests declared.

  13. Emmanuel Dias-Neto

    Laboratory of Computational Biology, A.C. Camargo Cancer Center, Sao Paulo, Brazil
    Competing interests
    Emmanuel Dias-Neto, The University of New Mexico filed patent applications on PRUNE2- related technology, for which Emmanuel Dias-Neto was an inventor (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreement terminated. No payments were made to Emmanuel Dias-Neto, and the author has no other competing interests to declare..

  14. Isan Chen

    MBrace Therapeutics, San Diego, United States
    Competing interests
    Isan Chen, serves as the Chief Executive Officer of MBrace Therapeutics. Mbrace did not provide financial support for the present work..

  15. Dennis J McCance

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  16. Webster K Cavenee

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    Webster K Cavenee, is a founder and shareholder of Interleukin Combinatorial Therapies, Inc., InVaMet, Inc., and io9, LLC; none of these companies provided funds or participated in the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institution. The author received support for attending the Aspen Cancer Conference, and participated in a Leadership or fiduciary role. The author holds a Leadership or fiduciary role at Genetron Health for which they receive board fees, and are on the Board of Directors for the GBM AGILE Clinical Trial. The author has no other competing interests to declare..

  17. Renata Pasqualini

    Department of Radiation Oncology, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    Renata Pasqualini, Reviewing editor, eLifeThe University of New Mexico filed patent applications on PRUNE2- related technology (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. RP (and WA) is a founder and equity stockholder of PhageNova Bio, Inc. and of MBrace Therapeutics, Inc.; RP also serves as a paid consultant and the Chief Scientific Officer of PhageNova Bio and as a paid consultant and member of the Board of Directors for MBrace Therapeutics. Mbrace did not provide financial support for the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institutions..

  18. Wadih Arap

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Newark, United States
    For correspondence
    wa116@newark.rutgers.edu
    Competing interests
    Wadih Arap, Reviewing editor, eLifeThe University of New Mexico filed patent applications on PRUNE2-related technology (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. WA is a founder and equity stockholder of PhageNova Bio, Inc. and of MBrace Therapeutics, Inc. Mbrace did not provide financial support for the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institutions..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8686-4584

Funding

National Cancer Institute (P30CA118100)

  • Richard C Lauer

National Cancer Institute (P30CA072720)

  • Renata Pasqualini
  • Wadih Arap

Levy-Longenbaugh Donor-Advised Fund

  • Renata Pasqualini
  • Wadih Arap

Prostate Cancer Foundation

  • Renata Pasqualini
  • Wadih Arap

Brazilian National Council for Scientific and Technological Development

  • Emmanuel Dias-Neto

Associação Beneficente Alzira Denise Hertzog Silva

  • Emmanuel Dias-Neto

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: For the discovery cohort, there was University of New Mexico Health Sciences Institutional Review Board (IRB) approval (HRRC15-138), and the study was carried out in accordance with the United States Common Rule. As the discovery cohort involved secondary use of archival biospecimens, the IRB waived the requirement for informed consent .

Copyright

© 2023, Lauer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 624
    views
  • 117
    downloads
  • 2
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap
(2023)
Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
eLife 12:e81929.
https://doi.org/10.7554/eLife.81929

Share this article

https://doi.org/10.7554/eLife.81929

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Medicine

    Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction

    Soo-Yeon Hwang, Kyung-Hwa Jeon ... Youngjoo Kwon
    Research Article

    HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success; however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab. In this study, we synthesized a total of 26 compounds consisting of 10 chalcones, 7 pyrazoline acetyl, and 9 pyrazoline propionyl derivatives, and evaluated their biological activity as potential ELF3-MED23 PPI inhibitors. Upon systematic analysis, candidate compound 10 was selected due to its potency in downregulating reporter gene activity of ERBB2 promoter confirmed by SEAP activity and its effect on HER2 protein and mRNA levels. Compound 10 effectively disrupted the binding interface between the ELF3 TAD domain and the 391–582 amino acid region of MED23, resulting in successful inhibition of the ELF3-MED23 PPI. This intervention led to a substantial reduction in HER2 levels and its downstream signals in the HER2-positive gastric cancer cell line. Subsequently, compound 10 induced significant apoptosis and anti-proliferative effects, demonstrating superior in vitro and in vivo anticancer activity overall. We found that the anticancer activity of compound 10 was not only restricted to trastuzumab-sensitive cases, but was also valid for trastuzumab-refractory clones. This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

    1. Medicine

    Enhancing bone regeneration and osseointegration using rhPTH(1-34) and dimeric R25CPTH(1-34) in an osteoporotic beagle model

    Jeong-Oh Shin, Jong-Bin Lee ... Jin-Woo Kim
    Research Article

    This study investigates the effects of two parathyroid hormone (PTH) analogs, rhPTH(1-34) and dimeric R25CPTH(1-34), on bone regeneration and osseointegration in a postmenopausal osteoporosis model using beagle dogs. Twelve osteoporotic female beagles were subjected to implant surgeries and assigned to one of three groups: control, rhPTH(1-34), or dimeric R25CPTH(1-34). Bone regeneration and osseointegration were evaluated after 10 weeks using micro-computed tomographic (micro-CT), histological analyses, and serum biochemical assays. Results showed that the rhPTH(1-34) group demonstrated superior improvements in bone mineral density, trabecular architecture, and osseointegration compared to controls, while the dimeric R25CPTH(1-34) group exhibited similar, though slightly less pronounced, anabolic effects. Histological and TRAP assays indicated both PTH analogs significantly enhanced bone regeneration, especially in artificially created bone defects. The findings suggest that both rhPTH(1-34) and dimeric R25CPTH(1-34) hold potential as therapeutic agents for promoting bone regeneration and improving osseointegration around implants in osteoporotic conditions, with implications for their use in bone-related pathologies and reconstructive surgeries.

    1. Medicine
    2. Neuroscience

    Blood metabolomic profiling reveals new targets in the management of psychological symptoms associated with severe alcohol use disorder

    Sophie Leclercq, Hany Ahmed ... Nathalie Delzenne
    Research Article

    Background:

    Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.

    Methods:

    In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.

    Results:

    We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.

    Conclusions:

    Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.

    Funding:

    Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.