Abstract 4341: Distinct expression of PMEPA1 and its isoform, STAG1 in prostate cancer
Authors: Li Hua , Ravindranath Lakshmi , Chen Yongmei , Sharad Shashwat , Dillman Allissa , Srinivasan Alargarsamy , McLeod David G. , Sesterhenn Isabell A. , Dobi Albert , Srivastava Shiv , Petrovics Gyorgy 
Published: August 2015

Introduction and Objectives: We have defined a feedback loop model for the regulation of androgen receptor (AR) degradation by the hormone inducible PMEPA1 through NEDD4 E3 ubiquitin ligase in prostate cancer (CaP). The characterization of PMEPA1 at the mRNA levels indicated five isoforms transcribed from distinct promoters within the PMEPA1 locus. Analysis of the amino acid sequences of all PMEPA1 isoforms indicated variations at the N- and/or C- termini of the protein. Based on the prediction algorithms, PMEPA1 is classified as a type 1b transmembrane protein. In order to better understand the role of PMEPA1 in CaP, this study focuses on comparative analyses of the two most abundant isoforms of PMEPA1 in human CaPs.

Methods: Androgen responsive LNCaP and VCaP cells were used to evaluate the expression levels of annotated PMEPA1 isoforms by quantitative RT-PCR and by RNA-Seq. For validating of the two most abundant forms, the isoform 1 (Solid Tumor Associated Gene 1, STAG1) and the isoform 2 (PMEPA1), prostate tumor and benign epithelial cells were laser capture microdissected (LCM) from frozen OCT embedded prostate tissue. Total RNA was isolated from the LCM samples of 117 matched normal and prostate tumor specimens (N = 234) and were analyzed by TaqMan-based QRT-PCR for PMEPA1 isoform-1(STAG1) and isoform 2 (PMEPA1), AR and PSA. Correlation of the gene expression data with clinical and pathological characteristics, including biochemical recurrence (BCR) were examined by Kaplan-Meier survival and Cox proportional hazard model analyses.

Results: We have identified four mRNAs transcribed from the PMEPA1 locus in VCaP and LNCaP transcriptomes. Among these, STAG1 was highly expressed followed by PMEPA1 in both VCaP and LNCaP cells. In CaP patients tumor (T) over normal (N) mRNA expression of STAG1 did not have significant correlation with transcript levels of PMEPA1, AR or PSA. Patients with increased STAG1 mRNA level had a shorter time to BCR in a Kaplan-Meier analysis (P = 0.018). The correlation of increased STAG1 expression in tumor cells with increased chance for BCR was supported by multivariable Cox proportional hazard model (P = 0.0015; HR = 4.3).

Conclusions: As expected from the distinct transcription initiation origin, there were no significant correlation between the T/N expression of PMEPA1 (isofom 2) and STAG1 in human CaP specimens. Intriguingly, STAG1 (isoform 1) expression was an independent predictor of BCR after radical prostatectomy that warrants further investigations.

Keywords: PMEPA1, STAG1, AR, prostate cancer, biochemical recurrence

Funding: This study was supported by NIH grant, CA106653 to SS and AD and CPDR, USUHS, HU0001-10-2-0002 to DGM.

Citation Format: Hua Li, Lakshmi Ravindranath, Yongmei Chen, Shashwat Sharad, Allissa Dillman, Alargarsamy Srinivasan, David G. McLeod, Isabell A. Sesterhenn, Albert Dobi, Shiv Srivastava, Gyorgy Petrovics. Distinct expression of PMEPA1 and its isoform, STAG1 in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4341. doi:10.1158/1538-7445.AM2015-4341