Dual-specificity phosphatase 4 (DUSP4), a MAP kinase phosphatase, has been regarded as a tumor suppressor gene in several cancers. However, high-level expression of DUSP4 is occasionally observed in specific cancers and its functional significance in carcinogenesis is not fully understood. In the present study, we showed that downregulation of DUSP4 suppressed the proliferation of cancer cell lines exhibiting high expression of DUSP4 by inducing apoptosis and cell cycle arrest at G2/M phase. Expression microarray analyses and pathway analyses revealed that downregulation of DUSP4 activated the p53 signaling pathway, and might be involved in cell growth suppression. Aberrant accumulation of p53 and induction of p53 downstream target genes were further investigated. Furthermore, cell growth suppression following downregulation of DUSP4 was markedly attenuated in p53-deleted cells established using the CRISPR/Cas9 system. These findings suggest that constitutive expression of DUSP4 in cancer cells contributes to enhanced proliferation through escape from apoptosis and cell cycle arrest. We propose that DUSP4 could be a novel therapeutic target for cancers overexpressing it.

MAP激酶磷酸酶双重特异性磷酸酶4（DUSP4）在几种癌症中被视为抑癌基因。但是，在特定的癌症中偶尔会观察到DUSP4的高水平表达，其在癌变中的功能意义尚不完全清楚。在本研究中，我们表明DUSP4的下调通过诱导G2 / M期的细胞凋亡和细胞周期停滞，抑制了DUSP4高表达的癌细胞系的增殖。表达微阵列分析和途径分析表明，DUSP4的下调激活了p53信号传导途径，并可能参与细胞生长抑制。进一步研究了p53的异常积累和p53下游靶基因的诱导。此外，在使用CRISPR / Cas9系统建立的p53缺失的细胞中，DUSP4下调后的细胞生长抑制显着减弱。这些发现表明，DUSP4在癌细胞中的组成型表达通过逃避凋亡和细胞周期停滞而有助于增强增殖。我们建议DUSP4可能是过表达癌症的新型治疗靶标。