Upregulation of KCNQ1OT1 Promotes Resistance to Stereotactic Body Radiotherapy in Lung Adenocarcinoma by Inducing ATG5/ATG12-mediated Autophagy Via MiR-372-3p

Stereotactic body radiotherapy (SBRT) has emerged as a standard treatment for non-small-cell lung cancer. However, its therapeutic advantages are limited with the development of SBRT resistance. The SBRT-resistant cell lines (A549/IR and H1975/IR) were established after exposure with hypofractionated irradiation. The differential lncRNAs were screened by microarray assay, then the expression was detected in LUAD tumor tissues and cell lines by qPCR. The influence on radiation response was assessed via in vitro and in vivo assays, and autophagy levels were evaluated by western blot and transmission electron microscopy. Bioinformatics prediction and rescue experiments were used to identify the pathways underlying SBRT resistance. High expression of KCNQ1OT1 was identified in LUAD SBRT-resistant cells and tissues, positively associated with a large tumor, advanced clinical stage, and a lower response rate to concurrent therapy. KCNQ1OT1 depletion significantly resensitized A549/IR and H1975/IR cells to radiation by inhibiting autophagy, which could be attenuated by miR-372-3p knockdown. Furthermore, autophagy-related 5 (ATG5) and autophagy-related 12 (ATG12) were confirmed as direct targets of miR-372-3p. Restoration of either ATG5 or ATG12 abrogated miR-372-3p-mediated autophagy inhibition and radiosensitivity. Our data describe that KCNQ1OT1 is responsible for SBRT resistance in LUAD through induction of ATG5- and ATG12-dependent autophagy via sponging miR-372-3p, which would be a potential strategy to enhance the antitumor effects of radiotherapy in LUAD.