DUSP4 is a biomarker of esophageal squamous cell carcinoma (ESCC), which is responsible for the prognosis in ESCC. However, the underlying mechanism of DUSP4-regulated ESCC carcinogenesis is unknown. As a negative regulator of JNK, DUSP4 can inhibit autophagy, which contributes to tumorigenesis. This study aimed to explore the role of autophagy in DUSP4-regulated ESCC carcinogenesis. Our results showed that DUSP4 overexpression inhibited autophagy and promoted LSD1 protein expression in ESCC cells, while DUSP4 silencing showed the opposite effects. However, DUSP4 overexpression and silencing did not affect LSD1 mRNA expression. But the regulatory ability of DUSP4 overexpression on autophagy, death level, and LSD1 protein was reversed by rapamycin. In addition, DUSP4 overexpression inhibited JNK and Bcl2 phosphorylation and the dissociation of Bcl2-Beclin1 complex, while DUSP4 silencing promoted JNK and Bcl2 phosphorylation. Moreover, the regulatory ability of DUSP4 overexpression on autophagy, death, and LSD1 protein was reversed by JNK activator anisomycin. The xenograft assays also showed that DUSP4 overexpression-promoted ESCC tumor growth in vivo and LC3II and LSD1 protein expression in tumor tissues were reversed by rapamycin or anisomycin. Overall, DUSP4 inhibits Bcl2-Beclin1-autophagy signal transduction through the negative regulation of JNK, thus suppressing autophagic death and the autophagic degradation of LSD1 in ESCC, by which DUSP4 promotes ESCC carcinogenesis.

DUSP4 是食管鳞状细胞癌 (ESCC) 的生物标志物，与 ESCC 的预后有关。然而，DUSP4 调节 ESCC 致癌的潜在机制尚不清楚。作为 JNK 的负调节因子，DUSP4 可以抑制自噬，从而促进肿瘤发生。本研究旨在探讨自噬在DUSP4调控的ESCC癌发生中的作用。我们的结果表明，DUSP4过表达抑制ESCC细胞中的自噬并促进LSD1蛋白表达，而DUSP4沉默则表现出相反的效果。然而，DUSP4 过表达和沉默并不影响 LSD1 mRNA 表达。但DUSP4过表达对自噬、死亡水平和LSD1蛋白的调节能力被雷帕霉素逆转。此外，DUSP4过表达抑制JNK和Bcl2磷酸化以及Bcl2-Beclin1复合物的解离，而DUSP4沉默促进JNK和Bcl2磷酸化。此外，DUSP4过表达对自噬、死亡和LSD1蛋白的调节能力被JNK激活剂茴香霉素逆转。异种移植试验还表明，DUSP4 过表达促进体内 ESCC 肿瘤生长，肿瘤组织中 LC3II 和 LSD1 蛋白表达被雷帕霉素或茴香霉素逆转。总体而言，DUSP4通过负向调节JNK抑制Bcl2-Beclin1-自噬信号转导，从而抑制ESCC中的自噬死亡和LSD1的自噬降解，从而促进ESCC的癌变。