The SELENOF Selenoprotein Localizes to the Outer Plasma Membrane in Human Prostatic Tissue and its Levels are Reduced in Prostate Cancer

Abstract

SELENOF (also referred to as Sep15) is a selenium containing protein shown to reside in the endoplasmic reticulum (ER). Previous studies have linked polymorphisms in SELENOF to prostate cancer mortality. To investigate the role of SELENOF inprostate cancer, human prostatic tissue obtained from patients following prostatectomy was examined by immunohistochemistry. Unlike what we observe inhuman cancer‐derived cell lines, SELENOF partitioned predominantly to the outercell membrane in histologically benign glands distal to the tumor. Similarly, outer membrane staining was observed when primary human epithelial cells were examined by confocal microscopy. The pattern of expression in tumors was dramatically different than that observed in benign tissue with the levels of the protein being significantly lower and generally not in the outer membrane. AfricanAmerican men are at an increased risk of prostate cancer. A functional polymorphism in SELENOF expected to result in lower SELENOF levels is approximately 5‐fold more prevalent in African Americans. Therefore, the levels of SELENOF were compared between tumor tissue obtained from African Americans(n=33) and Caucasians (n=295). SELENOF levels were lower in tumor cells from African Americans when the signals were evaluated from the entire cell (P<0.02). These results indicate that SELENOF may have a non‐ER function in normal prostate epithelia and lower levels in tumor tissue may be contributing to prostate cancer risk. Tissue SELENOF levels are likely to be responsive to an individual's selenium status and SELENOF genotype. Selenium levels in plasma obtained from 129 men who had undergone a prostatectomy and participated in a Chicago‐based study were genotyped for SELENOF and plasma selenium levels were evaluated. The genetic data obtained confirmed the higher frequency of the allele likely to result in lower SELENOF levels in AfricanAmericans and this allele was associated with both higher levels of the Prostate Specific Antigen (P<0.05) and the Gleason Score, a measure of prostate cancer aggressiveness and prognosis. The selenium status of AfricanAmerican men (115.24 ±3.04 ng/mL) in this cohort was also significantly lower (P<0.01) than that determined for Caucasians (139.18 ±2.41 ng/mL). Collectively, the data obtained from these two approaches indicates that the SELENOF genotype and the selenium status of individuals may be contributing to the disparate incidence and outcome of prostate cancer experienced by African American men.Support or Funding InformationThis work was supported by grants from the National Institutes of Health [Grant # RO1CA127943, R21CA182103] and a Research Supplement to Promote Diversity in Health‐Related Research to AMD.