Distinct Roles of SELENOF in Different Human Cancers

Abstract

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF’s discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF’s molecular mechanisms and its impact on cancer is warranted.

SELENOF Controls Proliferation and Cell Death in Breast-Derived Immortalized and Cancer Cells

“…Pathways enriched in genes negatively correlating with SELENOF included 'Mitotic Cell Cycle' and 'DNA Replication' (Figure 4B, left panel), while pathways enriched in genes positively correlating with SELENOF included 'Regulation of Cell Cycle' (Figure 4B, right panel). Other top enriched pathways were 'Translation', 'Endoplasmic Reticulum to Golgi Transport', and 'Protein Folding' (Figure 4B), which are consistent with previous reports of SELENOF's role in protein folding and redox quality control [11,17]. Together, these data indicate that the regulation of p21 and p27 contributes to SELENOF-driven effects on the cell cycle, proliferation, or cell death.…”

“…Intriguingly, SELENOF deficiency in HeLa cells affected the cell cycle by upregulating p21 and p27. These opposing consequences of SELENOF deficiency in cultured cells have been previously observed [17], although the reasons for the different tissue-specific outcomes remain unclear. In line with the SELENOF loss-induced reduction in p21 and p27, inhibition of CDK2 resulted in attenuated cell viability and increased cell death.…”

“…The observation that SELENOF is required for lumen formation in 3D cultures indicates its role in controlling both proliferation and cell death. Intriguingly, matrix-detached cells display dysregulation of metabolic activities and reactive oxygen species (ROS) [31], suggesting putative functions of SELENOF in redox and metabolism that may be relevant to breast tumorigenesis [17].…”

“…Given SELENOF's cellular localization within the EnR and its redox activity, it is postulated to play a putative role in disulfide-bond formation and protein redox quality control [10,11]. More recently, depletion of SELENOF in cultured human cells or in Selenof knockout animal models was shown to result in differential expression of metabolism-related genes and associated phenotypes [12][13][14][15][16][17]. In this study, SELENOF-driven functions and phenotypes were examined in normal breast epithelial and breast cancer cells to better understand the role of SELENOF in breast cancer and to identify potential new therapeutic strategies.…”

Deciphering the Role of Selenoprotein M

“…Another structural homolog found for SELENOM is SELENOF (previously named Sep15) [22,33]. Although their sequence identity is only 31%, SELENOF shares multiple regions of significant sequence identity to SELENOM [34].…”