Abstract：
Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy with increasing mortality and high recurrence. In this work, we aim to explore the functional role of NFE2 like bZIP transcription factor 1 (NFE2L1) in OSCC progression. Based on databases analysis, we found that NFE2L1 was overexpressed in OSCC tumor tissues, and elevated NFE2L1 level induced poor prognosis of OSCC patients. Our results showed that NFE2L1 is upregulated in OSCC cells and overexpression of NFE2L1 promotes cell proliferation, and reduces the sensitivity of OSCC cells to erastin-induced ferroptosis. NFE2L1 upregulation decreased the levels of Fe2+, lipid reactive oxygen species and content of malondialdehyde, and increased the level of the key negative regulator of ferroptosis, GPX4 and SLC7A11. In NFE2L1 suppressed cells, these trends were reversed. Further results of dual luciferase reporter and chromatin immunoprecipitation assays confirmed that NFE2L1 could bind to the promoter of Holliday junction recognition protein (HJURP) to increase the transcriptional activity of HJURP, thus upregulating its expression. Inhibition of HJURP attenuated the proliferation and ferroptosis inhibition in NFE2L1 upregulated cells. In vivo tumorigenicity assay further proved that NFE2L1 promotes OSCC tumor growth. In summary, NFE2L1 restrains ferroptosis by transcriptionally regulating HJURP and participates in the progress of OSCC. Thus, NFE2L1 plays a key role in OSCC development and may be a promising therapeutic target for OSCC.
摘要：
口腔鳞状细胞癌（OSCC）是一种常见的头颈部恶性肿瘤，死亡率增加，复发率高。在这项工作中,我们旨在探讨NFE2如bZIP转录因子1（NFE2L1）在OSCC进展中的功能作用。基于数据库分析，我们发现NFE2L1在OSCC肿瘤组织中过度表达，NFE2L1水平升高导致OSCC患者预后不良。我们的结果表明NFE2L1在OSCC细胞中上调，NFE2L1的过表达促进细胞增殖，并降低OSCC细胞对擦除素诱导的铁凋亡的敏感性。NFE2L1上调降低了Fe2+的水平，脂质活性氧和丙二醛含量，并增加了铁凋亡的关键负调节剂的水平，GPX4和SLC7A11。在NFE2L1抑制细胞中，这些趋势被逆转了。双荧光素酶报告基因和染色质免疫沉淀测定的进一步结果证实，NFE2L1可以与霍利迪连接识别蛋白（HJURP）的启动子结合，以增加HJURP的转录活性，从而提高了它的表达。HJURP的抑制减弱了NFE2L1上调细胞中的增殖和铁凋亡抑制。体内致瘤性检测进一步证明NFE2L1促进OSCC肿瘤生长。总之,NFE2L1通过转录调控HJURP抑制铁死亡，参与OSCC的进展。因此，NFE2L1在OSCC的发展中起着关键作用，并且可能是OSCC的有希望的治疗靶标。
