MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma
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Atul Ranjan1, Swathi V. Iyer1, Christopher Ward1, Tim Link1, Francisco J. Diaz2, Animesh Dhar1, Ossama W. Tawfik3, Steven A. Weinman4, Yoshiaki Azuma5, Tadahide Izumi6 and Tomoo Iwakuma1,7
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
2Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
3Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA
4Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
5Department of Molecular Bioscience, University of Kansas, Lawrence, KS, USA
6Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA
7Children’s Research Institute, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA
Keywords: MDM2; MTBP; Erk1/2; Elk-1; metastasis
Received: November 08, 2017 Accepted: March 21, 2018 Published: April 20, 2018
MTBP suppresses HCC migration by inhibiting the Erk1/2-Elk-1 signaling via competitive binding with an Erk1/2-tranporter, IPO7.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the prognosis of HCC patients, especially those with metastasis, remains extremely poor. This is partly due to unclear molecular mechanisms underlying HCC metastasis. Our previous study indicates that MDM2 Binding Protein (MTBP) suppresses migration and metastasis of HCC cells. However, signaling pathways regulated by MTBP remain unknown. To identify metastasis-associated signaling pathways governed by MTBP, we have performed unbiased luciferase reporter-based signal array analyses and found that MTBP suppresses the activity of the ETS-domain transcription factor Elk-1, a downstream target of Erk1/2 MAP kinases. MTBP also inhibits phosphorylation of Elk-1 and decreases mRNA expression of Elk-1 target genes. Reduced Elk-1 activity is caused by inhibited nuclear translocation of phosphorylated Erk1/2 (p-Erk) by MTBP and subsequent inhibition of Elk-1 phosphorylation. We also reveal that MTBP inhibits the interaction of p-Erk with importin-7/RanBP7 (IPO7), an importin family member which shuttles p-Erk into the nucleus, by binding to IPO7. Moreover, high levels of MTBP in human HCC tissues are correlated with cytoplasmic localization of p-Erk1/2. Our study suggests that MTBP suppresses metastasis, at least partially, by down-modulating the Erk1/2-Elk-1 signaling pathway, thus identifying a novel regulatory mechanism of HCC metastasis by regulating the subcellular localization of p-Erk.
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