title: Expression and Role of PAICS, a De Novo Purine Biosynthetic Gene in Prostate Cancer.
abstract: Our goal was to investigate de novo purine biosynthetic gene PAICS expression and evaluate its role in prostate cancer progression.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Balabhadrapatruni V S K
authors.initials: BV
authors.lastname: Chakravarthi
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Moloy T
authors.initials: MT
authors.lastname: Goswami
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Satya S
authors.initials: SS
authors.lastname: Pathi
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dodson
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Darshan S
authors.initials: DS
authors.lastname: Chandrashekar
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sumit
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sai Akshaya
authors.initials: SA
authors.lastname: Hodigere Balasubramanya
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.|Department of Urology, University of Michigan, Ann Arbor, Michigan.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002645:Chickens; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D010453:Peptide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014176:Protein Biosynthesis / Q000502:physiology; D011687:Purines / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D011687:Purines; D010453:Peptide Synthases; C022379:phosphoribosylaminoimidazole-succinocarboxamide synthetase; C030985:purine
keywords: MYC; PAICS; metastasis; prostate cancer; xenograft