MP24-03 METHYLATION OF THE PMEPA1 GENE DISRUPTS THE CONTROL OF ANDROGEN RECEPTOR IN PROSTATE CANCER (2014)

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-03 METHYLATION OF THE PMEPA1 GENE DISRUPTS THE CONTROL OF ANDROGEN RECEPTOR IN PROSTATE CANCER Shashwat Sharad, Hua Li, Lakshmi Ravindranath, Michael Haffner, Daniel Heidenberg, Srinivasan Yegnasubramanian, Yongmei Chen, Ahmed Mohamed, Alagarsamy Srinivasan, Gyorgy Petrovics, Albert Dobi, and Shiv Srivastava Shashwat SharadShashwat Sharad More articles by this author , Hua LiHua Li More articles by this author , Lakshmi RavindranathLakshmi Ravindranath More articles by this author , Michael HaffnerMichael Haffner More articles by this author , Daniel HeidenbergDaniel Heidenberg More articles by this author , Srinivasan YegnasubramanianSrinivasan Yegnasubramanian More articles by this author , Yongmei ChenYongmei Chen More articles by this author , Ahmed MohamedAhmed Mohamed More articles by this author , Alagarsamy SrinivasanAlagarsamy Srinivasan More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , Albert DobiAlbert Dobi More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.284AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Introduction: Androgen responsive PMEPA1 has been shown to recruit NEDD4-1, an E3 ubiquitin ligase, to degrade AR. Decreased or absent PMPEA1 expression was observed in more than 65% of prostate tumors. We hypothesized that methylation of PMEPA1 gene may contribute to silencing of PMEPA1, and decreased expression of PMEPA1 lead to enhance AR functions and accelerated prostate tumorigenesis. In this study, we defined the role of PMEPA1 gene methylation and evaluated the regulation of AR protein and AR signaling in response to inhibitors of the AR pathway. METHODS Methods: Methylation of the PMEPA1 gene was evaluated in LCM-enriched tumor samples by combing precipitation of methylated-DNA and methylation-sensitive restriction enzyme digestion (COMPARE-MS). The transcript levels of PMEPA1 gene was assessed by qRT-PCR. PMEPA1 was silenced by PMEPA1 Mission shRNA lentivirus. Cell growth, cell cycle, BrdU incorporation, colony plating efficiency and cell growth in soft agar were assessed in PMEPA1 depleted LNCaP cells in the presence or absence of MDV3100, bicalutamide and the synthetic androgen R1881. RESULTS Results: Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell population indicated significant correlation in prostate cancer (n=77, P=0.001). We noticed higher frequency of PMEPA1 gene methylation in prostate tumor of Caucasian men. PMEPA1 depleted LNCaP demonstrated more resistance to the growth inhibitory effects of MDV3100 and bicalutamide in R1881 treated hormone-depleted medium. PMEPA1 depleted cells demonstrated stronger BrdU incorporation abilities, cell plating efficiency as well as enhanced colony formation capacities in soft agar in MDV3100 and bicalutamid treated cells when compared to controls. The half life of androgen receptor (AR) was increased in PMEPA1 depleted LNCaP cells both in the absence and presence of MDV3100 and bicalutamide. CONCLUSIONS Conclusions: Silencing of PMEPA1 that normally maintains the AR levels may contribute to AR activation in prostate cancer cells. These data highlight that PMEPA1 deficiency may confer resistance to AR inhibitors during prostate cancer progression. Moreover, PMEPA1 depleted prostate cancer cells are more resistant to MDV3100 and bicalutamide due to enhanced AR signaling. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e260 Advertisement Copyright & Permissions© 2014Metrics Author Information Shashwat Sharad More articles by this author Hua Li More articles by this author Lakshmi Ravindranath More articles by this author Michael Haffner More articles by this author Daniel Heidenberg More articles by this author Srinivasan Yegnasubramanian More articles by this author Yongmei Chen More articles by this author Ahmed Mohamed More articles by this author Alagarsamy Srinivasan More articles by this author Gyorgy Petrovics More articles by this author Albert Dobi More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...