Identifying polymorphic cis-regulatory variants as risk markers for lung carcinogenesis and chemotherapy responses in tobacco smokers from eastern India

Aberrant expression of xenobiotic metabolism and DNA repair genes is critical to lung cancer pathogenesis. This study aims to identify the cis-regulatory variants of the genes modulating lung cancer risk among tobacco smokers and altering their chemotherapy responses. From a list of 2984 SNVs, prioritization and functional annotation revealed 22 cis-eQTLs of 14 genes within the gene expression-correlated DNase I hypersensitive sites using lung tissue-specific ENCODE, GTEx, Roadmap Epigenomics, and TCGA datasets. The 22 cis-regulatory variants predictably alter the binding of 44 transcription factors (TFs) expressed in lung tissue. Interestingly, 6 reported lung cancer-associated variants were found in linkage disequilibrium (LD) with 5 prioritized cis-eQTLs from our study. A case–control study with 3 promoter cis-eQTLs (p < 0.01) on 101 lung cancer patients and 401 healthy controls from eastern India with confirmed smoking history revealed an association of rs3764821 (ALDH3B1) (OR = 2.53, 95% CI = 1.57–4.07, p = 0.00014) and rs3748523 (RAD52) (OR = 1.69, 95% CI = 1.17–2.47, p = 0.006) with lung cancer risk. The effect of different chemotherapy regimens on the overall survival of lung cancer patients to the associated variants showed that the risk alleles of both variants significantly decreased (p < 0.05) patient survival

Spatial Position Regulates Power of Tryptophan: Discovery of a Major-Groove-Specific Nuclear-Localizing, Cell-Penetrating Tetrapeptide

Identification of key amino acids is required for development of efficient cell-penetrating peptides (CPPs) and has tremendous implications in medicine. Extensive research work has enlightened us about the importance of two amino acids, arginine and tryptophan, in cell penetration. Here, we present a top-down approach to show how spatial positions of two tryptophans regulate the cellular entry and nuclear localization. This enables us to develop short, non-toxic tetrapeptides with excellent potential for cell penetration and nuclear localization. Among them, Glu-Thr-Trp-Trp (ETWW) emerges as the most promising. Results suggest that it enters into cancer cells following an endocytic pathway and binds at the major groove of nuclear DNA, where successive tryptophan plays major role. We subsequently show that it is not a P-glycoprotein substrate and is non-toxic to PC12-derived neurons, suggesting its excellent potential as a CPP. Furthermore, its potential as a CPP is validated in multi-cellular 3D cell culture (spheroid) and in <i>in vivo</i> mice model. This study provides major fundamental insights about the positional importance of tryptophan and opens new avenues toward the development of next-generation CPPs and major-groove-specific anticancer drugs