Combatting cellular immortality in cancers by targeting the shelterin protein complex

Shelterin proteins (TERF1, TERF2, TPP1, TINF2, POT1) protect telomeres, prevent unwarranted repair activation, and regulate telomerase activity. Alterations in these proteins can lead to cancer progression. This study uses an in-silico approach to examine shelterin in tumour samples across various cancers, employing mutation plots, phylogenetic trees, and sequence alignments. Network pharmacology identified TERF1 as an essential shelterin protein and transcription factors RUNX1, CTCF, and KDM2B as potential biomarkers due to their interactions with miRNAs and shelterin proteins. We performed MCODE analysis to identify subnetworks of ncRNAs interacting with the shelterin proteins. Shelterin expression predicted patient survival in 24 cancer types, with TERF1, TERF2, TINF2, and POT1 significantly expressed in testicular, AML, prostate, breast and renal cancers, respectively, and TPP1 in AML and skin cancer. Spearman and Pearson's analyses showed significant correlations of TERF1 across cancers, with near-significant correlations for all five proteins in different cancer datasets like breast cancer, kidney renal papillary and lung squamous cell carcinoma, skin cutaneous melanoma, etc.,. Shelterin expression correlated with patient survival in breast, renal, lung, skin, uterine, and gastric cancers. Insights into TPP1-associated glycans highlighted glycosylated sites contributing to tumorigenesis. This study provides molecular signatures for further functional and therapeutic research on shelterin, highlighting its potential as a target for anti-cancer therapies and promising prospects for cancer prognosis and prediction.