Expression and role of PAICS, a de novo purine biosynthetic gene in prostate cancer
Autor: | Sooryanarayana Varambally, Nallasivam Palanisamy, Arul M. Chinnaiyan, Balabhadrapatruni V. S. K. Chakravarthi, Darshan S. Chandrashekar, Robert J. Lonigro, Moloy T. Goswami, Javed Siddiqui, Sumit Agarwal, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Satya S. Pathi, Matthew Dodson, Lakshmi P. Kunju |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Urology Mice Nude Biology Gene Expression Regulation Enzymologic Metastasis 03 medical and health sciences Prostate cancer Mice DU145 Prostate Cell Line Tumor LNCaP medicine Biomarkers Tumor Animals Humans Neoplasm Invasiveness Peptide Synthases Gene knockdown Phosphoribosylaminoimidazole carboxylase Prostatic Neoplasms medicine.disease Molecular biology Xenograft Model Antitumor Assays Bromodomain Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology Purines Protein Biosynthesis Chickens |
Zdroj: | The Prostate. 78(9) |
ISSN: | 1097-0045 |
Popis: | BACKGROUND Our goal was to investigate de novo purine biosynthetic gene PAICS expression and evaluate its role in prostate cancer progression. METHODS Next-generation sequencing, qRTPCR and immunoblot analysis revealed an elevated expression of a de novo purine biosynthetic gene, Phosphoribosylaminoimidazole Carboxylase, Phosphoribosylaminoimidazole Succinocarboxamide Synthetase (PAICS) in a progressive manner in prostate cancer. Functional analyses were performed using prostate cancer cell lines- DU145, PC3, LnCaP, and VCaP. The oncogenic properties of PAICS were studied both by transient and stable knockdown strategies, in vivo chicken chorioallantoic membrane (CAM) and murine xenograft models. Effect of BET bromodomain inhibitor JQ1 on the expression level of PAICS was also studied. RESULTS Molecular staging of prostate cancer is important factor in effective diagnosis, prognosis and therapy. In this study, we identified a de novo purine biosynthetic gene; PAICS is overexpressed in PCa and its expression correlated with disease aggressiveness. Through several in vitro and in vivo functional studies, we show that PAICS is necessary for proliferation and invasion in prostate cancer cells. We identified JQ1, a BET bromodomain inhibitor previously implicated in regulating MYC expression and demonstrated role in prostate cancer, abrogates PAICS expression in several prostate cancer cells. Furthermore, we observe loss of MYC occupancy on PAICS promoter in presence of JQ1. CONCLUSIONS Here, we report that evaluation of PAICS in prostate cancer progression and its role in prostate cancer cell proliferation and invasion and suggest it as a valid therapeutic target. We suggest JQ1, a BET-domain inhibitor, as possible therapeutic option in targeting PAICS in prostate cancer. Prostate. © 2016 Wiley Periodicals, Inc. |
Databáze: | OpenAIRE |
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