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

Li Ting Wang, Kwei Yan Liu, Shyh Shin Chiou, Shau Ku Huang, Shih Hsien Hsu*, Shen Nien Wang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)160-171
Number of pages12
JournalCancer Letters
Volume520
DOIs
Publication statusPublished - 2021 Nov 1

Keywords

  • Hepatocellular carcinoma (HCC)
  • ISX
  • MAPK
  • Nuclear translocation
  • Tyrosine kinase inhibitors (TKIs)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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