Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

SIMPLE SUMMARY: Telomeres are the protective caps at the ends of chromosomes, and they are maintained by an enzyme called telomerase. Telomerase activity allows rapid reproduction of the cells (proliferation) of the lining of the womb (endometrium). Telomerase levels are high in cancers in general, including in endometrial cancer. Dyskerin is one of the main components of the telomerase enzyme. While the other main components of telomerase have been studied in endometrial cancer, there are no previous studies on dyskerin in the endometrium. Our study shows that dyskerin levels are significantly lower in endometrial cancer and levels are linked to the survival of women. Experimentally increasing dyskerin protein in endometrial cells in the laboratory reduces the rate of cell proliferation. Consequently, we propose that dyskerin may be a regulator of endometrial cancer cell proliferation, and further studies are required to test if it can be targeted to develop new therapies for endometrial cancer. ABSTRACT: Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. We aimed to examine the expression, prognostic relevance, and functional role of dyskerin in human EC. Endometrial samples from a cohort of 175 women were examined with immunohistochemistry, immunoblotting, and qPCR. The EC cells were transfected with Myc-DDK-DKC1 plasmid and the effect of dyskerin overexpression on EC cell proliferation was assessed by flow cytometry. Human endometrium expresses dyskerin (DKC1) and dyskerin protein levels are significantly reduced in ECs when compared with healthy postmenopausal endometrium. Low dyskerin immunoscores were potentially associated with worse outcomes, suggesting a possible prognostic relevance. Cancer Genome Atlas (TCGA) ECs dataset (n = 589) was also interrogated. The TCGA dataset further confirmed changes in DKC1 expression in EC with prognostic significance. Transient dyskerin overexpression had a negative effect on EC cell proliferation. Our data demonstrates a role for dyskerin in normal endometrium for the first time and confirms aberrant expression with possible prognostic relevance in EC. Interventions aimed at modulating dyskerin levels may provide novel therapeutic options in EC.