PT - JOURNAL ARTICLE AU - Sun, Qi AU - Chen, Danqi AU - Raja, Amna AU - Grunig, Gabriele AU - Zelikoff, Judith AU - Jin, Chunyuan TI - Downregulation of Stem-loop binding protein by nicotine <em>via</em> α7-nicotinic acetylcholine receptor and its role in nicotine-induced cell transformation AID - 10.1101/2022.03.21.485231 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.03.21.485231 4099 - http://biorxiv.org/content/early/2022/03/21/2022.03.21.485231.short 4100 - http://biorxiv.org/content/early/2022/03/21/2022.03.21.485231.full AB - The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nAChR (nicotinic acetylcholine receptors) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, not only CDK1 and CK2, two kinases well known for their function for SLBP phosphorylation and degradation, but also CDK2 and PI3K/AKT pathways are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.Competing Interest StatementThe authors have declared no competing interest.