Loss of SELENOF Induces the Transformed Phenotype in Human Immortalized Prostate Epithelial Cells

Abstract

SELENOF is a member of the class of selenoproteins in which the amino acid selenocysteine is co-translationally inserted into the elongating peptide in response to an in-frame UGA codon located in the 3′-untranslated (3′-UTR) region of the SELENOF mRNA. Polymorphisms in the 3′-UTR are associated with an increased risk of dying from prostate cancer and these variations are functional and 10 times more frequent in the genomes of African American men. SELENOF is dramatically reduced in prostate cancer compared to benign adjacent regions. Using a prostate cancer tissue microarray, it was previously established that the reduction of SELENOF in the cancers from African American men was significantly greater than in cancers from Caucasian men. When SELENOF levels in human prostate immortalized epithelial cells were reduced with an shRNA construct, those cells acquired the ability to grow in soft agar, increased the ability to migrate in a scratch assay and acquired features of energy metabolism associated with prostate cancer. These results support a role of SELENOF loss in prostate cancer progression and further indicate that SELENOF loss and genotype may contribute to the disparity in prostate cancer mortality experienced by African American men.

Distinct Roles of SELENOF in Different Human Cancers

“…Recent data indicate that the depletion of SELENOF in cultured human cells or in Selenof KO animal models leads to differential expression of metabolism-related genes and associated phenotypes. Using immortalized human prostate epithelial cells, knockdown of SELENOF with an siRNA construct resulted in increased mitochondrial respiration and presumably ATP synthesis, increased phosphorylation and activation of AMP-activated protein kinase and inhibition by phosphorylation of acetyl CoA carboxylase, key proteins in regulating energy metabolism [ 50 ]. SELENOF was reported to bind to retinol dehydrogenase 11 and its overexpression led to reduced retinol production indicating that SELENOF may also play a role in vitamin A metabolism [ 51 ].…”

“…Additional interest in SELENOF in relation to prostate cancer was sparked by the observation that polymorphisms in SELENOF gene were associated with prostate cancer mortality among participants of the Physician’s Health Study [ 58 ]. Examination of human prostate tissue from two different tissue microarrays indicated that SELENOF co-localized with the plasma membrane in benign prostate tissue and immortalized human prostate cells in contrast to its location in other tissues where it resides in the EnR [ 38 , 50 ]. Moreover, SELENOF levels were significantly lower in prostate cancer samples compared to adjacent benign tissue, raising the possibility that the loss of SELENOF in prostate cancer was contributing to oncogenic progression.…”

“…Moreover, SELENOF levels were significantly lower in prostate cancer samples compared to adjacent benign tissue, raising the possibility that the loss of SELENOF in prostate cancer was contributing to oncogenic progression. Support for this was obtained from cell culture studies where it was established that reducing SELENOF in RWPE-1 immortalized prostate epithelial cells resulted in the acquisition of the ability to grow in soft agar and enhanced migration as determined with the scratch assay [ 50 ]. Most cancer cells shift their energy needs to aerobic glycolysis with an increased rate of glucose uptake and lactate production, referred to as the Warburg effect [ 59 ].…”

“…However, normal prostate cells rely heavily on glycolysis to divert the metabolic intermediates for the production of citrate that is required to maintain sperm health [ 60 ]. Attenuating the production of SELENOF in RWPE-1 cells resulted in a shift in decreased oxygen consumption and phosphorylation of regulatory proteins that promote glycolysis, thus being more typical of prostate cancer cells [ 50 ]. A review of the effects of altering SELENOF levels on energy metabolism in prostate cells has recently been published [ 61 ].…”

Editorial to Special Issue Molecular Biology of Selenium in Health and Disease

“…Furthermore, selenium deficiency is discussed in the setting of cardiovascular function [ 6 ] and as a trigger for autoimmune diseases [ 7 ]. This Special Issue also provides insights into selenoprotein mechanisms, including SELENOF in prostate [ 8 ] and colon cancers [ 9 ], SELENOI in immune response [ 10 ], SELENOW’s interaction with thioredoxins [ 11 ], and SELENOP-mediated selenium transport in Hashimoto`s thyroiditis [ 12 ]. Furthermore, an overview of the pathogenic variants in selenoproteins genes from a population genomics perspective [ 13 ], a review on the human genetic disorders resulting in systemic selenoprotein deficiency [ 14 ], and a new strategy to assess the selenoproteome by non-radioactive isotopic labeling are presented [ 15 ].…”