Non-small cell lung cancer (NSCLC), a heterogeneous disease, is a prevalent and malignant tumor with high cancer-related mortality [1]. Early diagnosis of NSCLC is difficult and most of patients develop into the advanced stages [2]. Meanwhile, radioresistance is the primary cause of the decreased curability and poor survival in patients receiving definitive radiation therapy [3]. The previous studies have indicated the potential of molecular biomarkers in elevating therapeutic responses of tumors including NSCLC [4], [5]. Thus, a profound investigation of the pathogenic mechanism and radiosensitivity regulation underlying NSCLC to identify the therapeutic target is necessary.

Ubiquitin-specific protease 5 (USP5) is a deubiquitinating enzyme (DUB) implicated in the protein metabolic pathway through disassembling the polyubiquitin chains on degraded proteins into ubiquitin monomers [6]. USP5 has been found to function as a tumorigenic factor in gastric cancer, and targeting USP5 can overcome chemoresistance via regulating p53 [7]. Also, USP5 was shown to promote lung cancer stemness and metastasis via deubiquitination of β-catenin [8]. Homeobox A10 (HOXA10) was identified as an oncogenic gene in various cancer types. For example, HOXA10 promoted proliferation and reduced apoptosis in esophageal cancer [9]; HOXA10 contributed to gastric cancer metastasis and progression [10]. In addition, a study on lung adenocarcinoma showed that HOXA10 was overexpressed, and its knockdown suppressed cell migration and invasion [11]. The association between oncogenic USP5 and HOXA10 in NSCLC remains unclear. Thus, it is essential to explore whether USP5 can mediate deubiquitination of HOXA10.

Specificity protein 1 (SP1) is a well-known transcription factor with important implications in various biological processes [12]. SP1 could bind to the promoter region of PIK3CB and enhance transcription to promote gastric carcinogenesis [13]. SP1 was reported as an oncogene to enhance proliferation and inhibit ferroptosis in NSCLC cells, and it interacted with the POLE2 promoter [14]. Online database has predicted the binding between SP1 and HOXA10 promoter. Thus, it is necessary to explore whether SP1 can promote transcription of HOXA10.

This study focused on the deubiquitination effect of USP5 on HOXA10 in NSCLC. Meanwhile, the roles of USP5 and HOXA10 in regulating cell biological behaviors and radiosensitivity were investigated. In addition, SP1-induced transcription regulation for HOXA10 was first studied. Herein, the objective was to explore the different mechanisms of HOXA10. HOXA10 might be used as a potential target for NSCLC treatment, particularly in improving radiosensitivity of NSCLC.