Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in east Asia. However, the molecular mechanism underlying its progression remains unclear. The ubiquitin-proteasome system (UPS) is a central mechanism for protein degradation and turnover. Accumulating evidence showed that more and more deubiquitinases could serve as attractive anti-cancer target. The expression of USP14 and UCH37 in esophagus squamous cell carcinoma tissues were examined by immunohistochemistry and western blot assays. Effect of b-AP15, a USP14 and UCH37 inhibitor, on ESCC cell growth was evaluated by cell viability assay. After cell lines being treated with b-AP15, cell cycle, apoptosis and the expression of related proteins were further explored to investigate the anti-ESCC mechanism of b-AP15. Results showed that deubiquitinating enzymes (DUBs) USP14 and UCH37 expressed at higher levels in ESCC tissues than in adjacent tissues. b-AP15 could inhibit cell proliferation and induce G2/M cell cycle arrest and apoptosis in ESCC cells. Mechanistically, b-AP15 treatment triggered Noxa-dependent apoptosis, which was regulated by c-Myc. Silencing Noxa and c-Myc could reduce b-AP15-induced apoptosis in ESCC cells. Our results revealed a novel mechanism of anti-tumor activity of b-AP15 in ESCC, and b-AP15 could be used as a potential therapeutic agent in ESCC.

中文翻译：

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去泛素化酶抑制剂b-AP15诱导食管鳞状细胞癌中c-Myc-Noxa介导的细胞凋亡。

食管鳞状细胞癌（ESCC）是东亚地区最恶性的肿瘤之一。然而，其进展的分子机制仍不清楚。泛素-蛋白酶体系统（UPS）是蛋白质降解和周转的主要机制。越来越多的证据表明，越来越多的去泛素酶可以作为有吸引力的抗癌靶标。通过免疫组织化学和蛋白质印迹法检测USP14和UCH37在食道鳞状细胞癌组织中的表达。通过细胞生存力测定评估了b-AP15（一种USP14和UCH37抑制剂）对ESCC细胞生长的影响。用b-AP15处理细胞系后，进一步探索细胞周期，凋亡及相关蛋白的表达，以研究b-AP15的抗ESCC机制。结果显示，ESCP组织中的泛素化酶（DUB）USP14和UCH37的表达水平高于邻近组织。b-AP15可以抑制细胞增殖并诱导ESCC细胞G2 / M细胞周期阻滞和凋亡。从机制上讲，b-AP15处理触发了Noxa依赖性细胞凋亡，该凋亡受c-Myc调控。沉默Noxa和c-Myc可以减少b-AP15诱导的ESCC细胞凋亡。我们的结果揭示了b-AP15在ESCC中具有抗肿瘤活性的新机制，而b-AP15可以作为ESCC中潜在的治疗剂。沉默Noxa和c-Myc可以减少b-AP15诱导的ESCC细胞凋亡。我们的结果揭示了b-AP15在ESCC中具有抗肿瘤活性的新机制，而b-AP15可以作为ESCC中潜在的治疗剂。沉默Noxa和c-Myc可以减少b-AP15诱导的ESCC细胞凋亡。我们的结果揭示了b-AP15在ESCC中具有抗肿瘤活性的新机制，而b-AP15可以作为ESCC中潜在的治疗剂。