Abstract
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is involved in cell proliferation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms linking gene expression and tumor formation remain unclear. In this study, we found that ISX transcriptionally activated E2F transcription factor 1 (E2F1) and associated oncogenic activity by directly binding to the E2 site of its promoter. Forced expression of ISX increased the expression of and phosphorylated the serine residue at position 332 of E2F1, which may be translocated into the nucleus to form the E2F1–DP-1 complex, suggesting that the promotion of oncogenic activities of the ISX–E2F1 axis plays a critical role in hepatoma cells. Coexpression of ISX and E2F1 significantly promoted p53 and RB-mediated cell proliferation and anti-apoptosis, and repressed apoptosis and autophagy. In contrast, short hairpin RNAi-mediated attenuation of ISX and E2F1 decreased cell proliferation and malignant transformation, respectively, in hepatoma cells in vitro and in vivo. The mRNA expression of E2F1 and ISX in 238 paired specimens from human HCC patients, and the adjacent, normal tissues exhibited a tumor-specific expression pattern which was highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. Therefore, our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression.
Highlights
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, regulates cell proliferation and drives hepatocellular carcinoma (HCC) formation via cyclin D1 upregulation under stimulation by proinflammatory cytokines such as IL-6 [1]
We show that ISX transcriptionally activates E2F transcription factor 1 (E2F1) expression by directly binding to the E2F1 promoter to activate the oncogenic activity of E2F1 via dissociation from retinoblastoma proteins 1 (RB1) and nuclear translocation
Our findings indicate that ISX is an important activator of E2F1 expression in HCC development
Summary
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, regulates cell proliferation and drives hepatocellular carcinoma (HCC) formation via cyclin D1 upregulation under stimulation by proinflammatory cytokines such as IL-6 [1]. E2F family transcription factors play key roles in cell cycle progression, apoptosis, cell differentiation, and stress response [2, 3]. E2F1 executes most of its biological functions through its ability to activate transcription in downstream genes involved in the cell cycle during the G1–S-phase transition, DNA synthesis and replication, checkpoint control, DNA damage and repair, apoptosis, autophagy, self-renewal, development, and differentiation [6, 7]. The cell cycle regulatory activity of E2F1 is controlled through the temporally regulated physical association of retinoblastoma proteins 1 (RB1), known as “pocket” proteins, with E2F subunits, whereby tumors with a deregulated E2F1/RB1 network cannot promote p53dependent apoptosis under conditions of p53 mutation or MDM2 overexpression [2]. E2F1 has recently been shown to be a fibrogenic protein that promotes liver fibrosis, a pre-stage of HCC, via interaction with SHP and its co-repressor EID1, to control Egr-1 expression in non-alcoholic and alcoholic liver fibrosis/cirrhosis [13]
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