Phosphorylation of intestine-specific homeobox by ERK1 modulates oncogenic activity and sorafenib resistance. (1st November 2021)

• Record Type: Journal Article
• Authors: Wang, Li-Ting; Liu, Kwei-Yan; Chiou, Shyh-Shin; Huang, Shau-Ku; Hsu, Shih-Hsien; Wang, Shen-Nien
• Is Part Of: Cancer letters. Volume 520(2021)
• Page Start: 160
• Page End: 171
• Publication Date: 2021-11-01
• Subjects: ISX -- MAPK -- Tyrosine kinase inhibitors (TKIs) -- Hepatocellular carcinoma (HCC) -- Nuclear translocation; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.07.011
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Nuclear translocation regulated by phosphorylation is a key step in providing activated mitogen-activated protein kinases (MAPKs) access to their nuclear targets; however, the mechanisms linking MAPK-induced nuclear translocation and target gene expression mediating oncologic activity remain obscure. Here, we show that the MAPK extracellular signal-regulated kinase (ERK) 1, but not ERK2, phosphorylated intestine-specific homeobox (ISX), leading to its nuclear translocation and downstream oncogenic signaling. Mechanistically, ERK1 phosphorylated serine 183 of ISX, facilitating its nuclear translocation and downstream target gene expression. In contrast, dominant-negative ERK1 expression in hepatoma cells inhibited the nuclear translocation of ISX and the expression of downstream genes involved in cell proliferation, malignant transformation, and epithelial-mesenchymal transition in vitro and in vivo . An activating mutation in ISX (S183D) exhibited a constitutive nuclear localization and resistance to sorafenib. Additionally, in 576 paired clinical hepatocellular carcinoma (HCC) samples and adjacent normal tissues, ERK1 and ISX were co-expressed in a tumor-specific manner at mRNA and protein levels, while their mRNA levels showed significant correlation with survival duration, tumor size, number, and stage. These results highlight the significance of ERK1/ISX signaling in HCC progression and its potential as a prognostic and therapeutic target in HCC. Highlights: ERK1 phosphorylated ISX, leading to its nuclear translocation and downstream oncogenic signaling. ERK1/ISX signaling in HCC progression and its potential as a prognostic and therapeutic target in HCC. An activating mutation in ISX (S183D) exhibited a constitutive nuclear localization and resistance to sorafenib.