USP18 Confers Paclitaxel Resistance in Non‐Small Cell Lung Cancer by Stabilizing SHANK1 Expression Via Deubiquitination

ABSTRACT Ubiquitin‐specific protease 18 (USP18) has been identified to promote lung cancer growth and metastasis by deubiquitinating protein substrates. Herein, the action and mechanism of USP18 on paclitaxel resistance in non‐small cell lung cancer (NSCLC) were investigated in this study. The mRNA and protein levels of USP18 and SH3 and multiple ankyrin repeat domains protein 1 (SHANK1) were detected by qRT‐PCR and western blot analysis analyses. PTX resistance in NSCLC cells was determined by analyzing cell proliferation, apoptosis, and IC50 values using colony formation assay, flow cytometry, and CCK‐8 assay, respectively. The glycolysis was determined by detecting glucose consumption, lactate production and ATP levels. Protein interaction was validated using Co‐IP assay. Cellular ubiquitination analyzed the deubiquitination effect of USP18 on SHANK1. Animal experiments was performed for in vivo analysis. USP18 was highly expressed in PTX‐resistant NSCLC tissues and cells. Silencing of USP18 promoted PTX sensitivity by suppressing the proliferation and glycolysis and inducing apoptosis in PTX‐resistant NSCLC cells. Mechanically, USP18 deubiquitinated SHANK1 and stabilized its expression. SHANK1 was highly expressed in PTX‐resistant NSCLC tissues and cells, and the deficiency of SHANK1 promoted the sensitivity of PTX‐resistant NSCLC cells to PTX. Moreover, the enhanced sensitivity of PTX‐resistant NSCLC cells to PTX that was caused by USP18 silencing could be reversed by SHANK1 overexpression. In addition, USP18 silencing reinforced PTX‐induced growth inhibition in NSCLC by regulating SHANK1. In conclusion, USP18 conferred paclitaxel resistance in NSCLC by stabilizing SHANK1 expression via deubiquitination.