Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the world. Radiotherapy is one of the standard therapies for patients with OSCC, but its clinical efficiency is limited due to radioresistance. In this study, we identified a mechanism of such resistance regulated by Ubiquitin-specific protease 14 (USP14). USP14 expression was significantly increased in clinical OSCC tissue samples and cell lines, and OSCC patients with high USP14 expression predicted poor overall survival rate. Additionally, a negative correlation between USP14 and LC3B was observed in patients with OSCC. We then found that irradiation (IR)-reduced cell survival of OSCC cells lines was further decreased when USP14 was knocked down. However, USP14 over-expression significantly promoted the cell viability of OSCC cells after IR treatment. Colony formation analysis confirmed thatafter IR treatment,USP14 knockdown markedly decreased the proliferation of OSCC cells, but over-expressing USP14 significantly up-regulated the proliferative activity of OSCC cells. Furthermore, DNA damage caused by IR was enhanced by USP14 knockdown, while been suppressed in OSCC cells with USP14 over-expression. Additionally, IR-inducedapoptosis was further promoted by USP14 knockdown in OSCC cells, which was, however, significantly abolished by USP14 over-expression.Moreover, our in vivo studies showed that IR-reduced tumor growth and tumor weight were further enhanced by USP14 knockdown in OSCC tumor-bearing nude mice. Finally, we found that USP14 knockdown could promote IR-induced autophagy by increasing LC3BII and γH2AX expression levels in IR-treated OSCC cells. However, this event was markedly abolished by ATG5 knockdown, subsequently restoring the cell proliferation in IR-incubated OSCC cells.Finally, we found that USP14-mediated apoptosis was autophagy-dependent in IR-treated OSCC cells. Taken together, these findings suggested that suppressing USP14 could alleviateradioresistancein OSCC both in vitro and in vivo by inducing apoptosis and autophagy, and thus could be served as a promising therapeutic strategy for OSCC treatment.

口腔鳞状细胞癌（OSCC）是世界上常见的恶性肿瘤。放射疗法是OSCC患者的标准疗法之一，但由于放射抵抗，其临床疗效受到限制。在这项研究中，我们确定了由泛素特异性蛋白酶14（USP14）调节这种抗性的机制。在临床OSCC组织样本和细胞系中，USP14的表达显着增加，并且USP14表达高的OSCC患者预测总体生存率较差。另外，在OSCC患者中观察到USP14和LC3B之间呈负相关。然后，我们发现敲除USP14后，OSCC细胞系的辐射（IR）降低的细胞存活率进一步降低。但是，USP14的过表达显着促进了IR处理后OSCC细胞的细胞活力。集落形成分析证实，IR处理后，USP14敲低显着降低了OSCC细胞的增殖，但过表达USP14显着上调了OSCC细胞的增殖活性。此外，IR引起的DNA损伤通过USP14敲低而增强，而在OSCC细胞中因USP14过表达而得到抑制。此外，OSP细胞中USP14的敲低进一步促进了IR诱导的细胞凋亡，但是USP14的过表达显着消除了IR诱导的细胞凋亡。体内研究表明，在OSCC荷瘤裸鼠中，USP14敲低可进一步提高IR减少的肿瘤生长和肿瘤重量。最后，我们发现USP14敲低可以通过增加IR处理的OSCC细胞中的LC3BII和γH2AX表达水平来促进IR诱导的自噬。然而，这一事件被ATG5敲除所取消，随后恢复了IR孵育的OSCC细胞中的细胞增殖。最后，我们发现USP14介导的凋亡在IR处理的OSCC细胞中是自噬依赖性的。总之，这些研究结果表明，抑制USP14可以既alleviateradioresistancein OSCC体外和体内通过诱导细胞凋亡和自噬，因此可以充当了OSCC治疗有前景的治疗策略。