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Characterizing the transcriptional regulation of importin α1 expression in non‐small cell lung cancer

KPNA2 (importin α1), an importin α family member is overexpressed and associated with cancer invasiveness in several types of human cancer. However, the upstream signaling as well as the transcription factor responsible for the regulation of KPNA2 expression remains unclear. Previously, we identified KPNA2 as a potential biomarker for non‐small cell lung cancer (NSCLC) and that mTOR signaling positively regulated Dp1/E2F1‐mediated transcription of KPNA2. We also found that KPNA2 might be involved in response to DNA damage stimulation, DNA metabolic processes, DNA repair and cell cycle. We herein show that interferon regulatory factor 1 (IRF1), a transcription factor with antitumor activity would suppress the expression of KPNA2 in NSCLC. The binding site of IRF1 in Kpna2 promoter was examined by chromatin immunoprecipitation assay. The ATM serine/threonine kinase inhibitor treatment dramatically induced the expression of IRF1, whereas significantly down‐regulated the expression of KPNA2 in NSCLC cells. Importantly, IRF1 knockdown restored the reducing level of KPNA2 in ATM inhibitor‐treated cells, supporting the suppressive role of IRF1 in regulation of KPNA2 expression. We also found that inhibiting either mTOR or ATM pathway significantly reduced the E2F1 expression but induced the IRF1 expression in vivo. Our result collectively show for the first time that IRF1 suppressed the KPNA2 expression and that two pathways, mTOR and ATM signaling might be involved in this IRF1‐mediated transcriptional regulation of KPNA2 expression in NSCLC.