Loss of Selenoprotein F Alters the Transformation Phenotype in Human Prostate Cancer Cells

Selenium is incorporated into selenoproteins in the form of the 21st amino acid selenocysteine that is coded by the UGA codon. Structures at the 3’ untranslated region of the selenoprotein mRNA known as the selenocysteine insertion sequence (SECIS) element redefines the UGA codon, normally coding for a stop codon, as a selenocysteine. This element recognizes and recruits the necessary components required for successful incorporation. Selenoprotein F (SELENOF, previously known as SEP15) is a 15 kDa protein that has been implicated in prostate cancer etiology due to the variants associated with prostate cancer mortality and reduced levels in prostate cancer compared to benign prostatic tissue. Currently, the function of SELENOF is unknown and only recent studies have associated its function with quality control of protein folding. In regard to the biological function in prostate cancer, the significance of the reduction of SELENOF remains to be elucidated. The current thesis provides evidence that the loss of SELENOF is not just a bystander and has biological consequences. The mechanism by which SELENOF levels are reduced in prostate cancer are unknown. Eukaryotic initiation factor 4A3 (eIF4a3) is involved in RNA splicing and involved in the formation of exon-exon junction, but has a secondary function of negatively regulating certain selenoproteins during times of low Se availability. Regulation of SELENOF by eIF4a3 has yet to be shown and some evidence of the relationship between these two proteins are provided in this thesis. In prostate cancer, eIF4a3 is dramatically increased compared to benign prostatic tissue and could explain the loss of SELENOF in prostate cancer.