Phosphorylation of intestine-specific homeobox by ERK1 modulates oncogenic activity and sorafenib resistance

• Published in: Cancer letters 2021-11, Vol.520, p.160-171
• Main Authors: Wang, Li-Ting, Liu, Kwei-Yan, Chiou, Shyh-Shin, Huang, Shau-Ku, Hsu, Shih-Hsien, Wang, Shen-Nien
• Format: Article
• Language: English
• Subjects: Animals; Biotechnology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell Line, Tumor; Cell proliferation; Drug resistance; Drug Resistance, Neoplasm - drug effects; Epithelial-Mesenchymal Transition - genetics; Extracellular signal-regulated kinase; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Hepatocellular carcinoma; Hepatocellular carcinoma (HCC); Hepatoma; Homeobox; Homeodomain Proteins - genetics; Humans; Inhibitor drugs; Intestine; Intestines - metabolism; ISX; Kinases; Laboratories; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Localization; Male; Manufacturers; MAP kinase; MAPK; Medical prognosis; Medical research; Mesenchyme; Metabolism; Mice; Mitogen-Activated Protein Kinase 3 - genetics; Monoclonal antibodies; Nuclear translocation; Nuclear transport; Phosphorylation; Polyclonal antibodies; Protein kinase; Proteins; Serine; Signal Transduction - drug effects; Sorafenib - pharmacology; Statistical analysis; Targeted cancer therapy; Therapeutic targets; Transcription Factors - genetics; Tyrosine kinase inhibitors (TKIs)
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.07.011

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. •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.