Expression and Role of PAICS, a De Novo Purine Biosynthetic Gene in Prostate Cancer.

Abstract

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 77:10-21, 2017. © 2016 Wiley Periodicals, Inc.

• Authors: Balabhadrapatruni V S K Chakravarthi, Moloy T Goswami, Satya S Pathi, Matthew Dodson, Darshan S Chandrashekar, Sumit Agarwal, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Javed Siddiqui, Robert J Lonigro, Arul M Chinnaiyan, Lakshmi P Kunju, Nallasivam Palanisamy, Sooryanarayana Varambally
• Journal: The Prostate (Prostate) Vol. 77 Issue 1 Pg. 10-21 (01 2017) ISSN: 1097-0045 [Electronic] United States
• PMID: 27550065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• Biomarkers, Tumor
• Purines
• Peptide Synthases
• phosphoribosylaminoimidazole-succinocarboxamide synthetase
• purine

Topics

• Animals
• Biomarkers, Tumor (biosynthesis, genetics)
• Cell Line, Tumor
• Chickens
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Invasiveness (pathology)
• Peptide Synthases (biosynthesis, genetics)
• Prostatic Neoplasms (enzymology, genetics, pathology)
• Protein Biosynthesis (physiology)
• Purines (biosynthesis)
• Xenograft Model Antitumor Assays (methods)