RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells

Manabu Muto,Ken Morita,Gengo Kashiwazaki,Moeka Obara,Tatsuki R Kataoka,Junichi Taniguchi,Masahiro Hirata,Souichi Adachi,Yasuhiko Kamikubo,Yasufumi Kaneda,Yoshihide Mitsuda,Toshikazu Bando,Pu Paul Liu,Hiroshi Sugiyama,Tatsutoshi Nakahata

doi:10.1038/s41598-018-24969-w

Abstract

The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein we report that RUNX1 regulates the ErbB2/HER2 signaling pathway in gastric cancer cells through transactivating SOS1 expression, rendering itself an ideal target in anti-tumor strategy toward this cancer. Mechanistically, RUNX1 interacts with the RUNX1 binding DNA sequence located in SOS1 promoter and positively regulates it. Knockdown of RUNX1 led to the decreased expression of SOS1 as well as dephosphorylation of ErbB2/HER2, subsequently suppressed the proliferation of gastric cancer cells. We also found that our novel RUNX inhibitor (Chb-M’) consistently led to the deactivation of the ErbB2/HER2 signaling pathway and was effective against several gastric cancer cell lines. Taken together, our work identified a novel interaction of RUNX1 and the ErbB2/HER2 signaling pathway in gastric cancer, which can potentially be exploited in the management of this malignancy.

Highlights

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related deaths in the world[1,2]
To investigate the underlying molecular mechanisms of RUNX1 in the tumorigenesis of gastric cancer cells, we conducted human phospho-Receptor tyrosine kinases (RTKs) array in MKN45 cells transduced with shRNA targeting RUNX1 or control luciferase and screened the relative phosphorylation levels of 49 RTKs in these samples
We have previously reported that the Cluster Regulation of RUNX (CROX) is a promising therapeutic strategy against various types of tumors including gastric cancer[22], precise molecular mechanisms of RUNX-inhibition-mediated anti-tumor effect on these malignant cells have poorly been elucidated

Summary

Introduction

Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related deaths in the world[1,2]. To investigate the underlying molecular mechanisms of RUNX1 in the tumorigenesis of gastric cancer cells, we conducted human phospho-RTK array in MKN45 cells transduced with shRNA targeting RUNX1 or control luciferase and screened the relative phosphorylation levels of 49 RTKs in these samples. We performed immunoblot experiment and validated that RUNX1-silencing dephosphorylated ErbB2/HER2 in the gastric cancer cells (Fig. 1e).

Results

Conclusion