FOX-A1 Contributes to Acquisition of Chemoresistance in Human Lung Adenocarcinoma via Transactivation of SOX5

Abstract

Background: Chemoresistance is a major obstacle for the effective treatment of lung adenocarcinoma (LAD). Forkhead box (FOX) proteins have recently been demonstrated to play critical roles in promoting epithelial-mesenchymal transition (EMT) and chemoresistance; however, it remains largely unknown whether FOX proteins contribute to the acquisition of EMT and chemoresistance in LAD. Methods: FOX-A1 expression were measured in LAD cells and tissues by qRT-PCR. The expression levels of EMT markers were detected by western blotting and immunofluorescence assay. Sex determining region Y-box protein 5 (SOX5) was identified as a novel and direct target of FOX-A1 via chromatin immunoprecipitation sequence (ChIP-seq) and Chromatin immunoprecipitation (ChIP) assay. Kaplan-Meier analysis and multivariate Cox regression analysis were performed to elucidate the significance of FOX-A1 and SOX5 expression in the prognosis of LAD patients. Findings: FOX-A1 was upregulated in docetaxel-resistant LAD cells that had been previously established, exhibited EMT-like characteristics and increased invasion phenotypes. High FOX-A1 expression was closely associated with a worse tumor response and poor prognosis and was significantly correlated with short progression-free survival (PFS) and overall survival (OS). SOX5 was identified as a new and direct target of FOX-A1 and also acted as an independent prognostic factor for poor PFS and OS in LAD patients. Knockdown of FOX-A1 and SOX5 reversed EMT tomesenchymal-epithelial transition (MET), attenuated metastatic characteristics and reversed the chemoresistance of docetaxel-resistant LAD cells. Interpretation: These data elucidate an original FOX-A1/SOX5 pathway that represents a promising therapeutic target for chemosensitizing LAD and provides predictive markers for evaluating the efficacy of chemotherapies. Funding: This work was supported by the National Natural Science Foundation of China (NO.81672928), Financial Grant from the China Postdoctoral Science Foundation (NO. 2018T110466 and NO.2017M621678), National Natural Science Foundation of China (NO.81702048, NO.81572345 and NO.81503528), the Suzhou Science and Technology Bureau project (No. SYS201609) and the Industrial Technology Innovation Project of Suzhou city (No. SYSD2016124). Declaration of Interest: The authors declare that there is no conflict of interest. Ethical Approval: This study was approved by the Review Board of Hospital Ethics Committee of Nanjing General Hospital of Nanjing Military Command (No. 2012-2-12-015, No. 2012-2-13-022, Nanjing General Hospital of Nanjing Military Command, Nanjing University, China) and conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all patients before specimen collection.