Erbin suppresses KSR1-mediated RaS/RAF signaling and tumorigenesis in colorectal cancer

Payton D. Stevens, Yang An Wen, Xiaopeng Xiong, Yekaterina Y. Zaytseva, Austin T. Li, Chi Wang, Ashley T. Stevens, Trevor N. Farmer, Tong Gan, Heidi L. Weiss, Masaki Inagaki, Sylvie Marchetto, Jean Paul Borg, Tianyan Gao

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colorectal cancer. Analysis of Erbin expression in colorectal cancer patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways. Erbin loss induced epithelial–mesenchymal transition, which coincided with a significant increase in cell migration and invasion. Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promoted tumorigenesis and significantly reduced survival. Tumor organoids derived from Erbin/Apc double knockout mice displayed increased tumor initiation potential and activation of Wnt signaling. Results from gene set enrichment analysis revealed that Erbin expression associated positively with the E-cadherin adherens junction pathway and negatively with Wnt signaling in human colorectal cancer. Taken together, our study identifies Erbin as a negative regulator of tumor initiation and progression by suppressing Akt and RAS/RAF signaling in vivo.

Original languageEnglish
Pages (from-to)4839-4852
Number of pages14
JournalCancer Research
Volume78
Issue number17
DOIs
StatePublished - Sep 1 2018

Bibliographical note

Funding Information:
We thank Dr. Emilia Galperin (University of Kentucky) for providing the expression construct of CFP-KSR1. This work was supported by R01CA133429 (T. Gao) and F31 CA196219 (P.D. Stevens). The studies were conducted with support provided by the Biospecimen Procurement and Translational Pathology and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). J.P, Borg's laboratory is funded by La Ligue Nationale Contre le Cancer (Label Ligue J.P. Borg), Fondation A*MIDEX, and SIRIC (INCa-DGOS-Inserm 6038).

Funding Information:
We thank Dr. Emilia Galperin (University of Kentucky) for providing the expression construct of CFP-KSR1. This work was supported by R01CA133429 (T. Gao) and F31 CA196219 (P.D. Stevens). The studies were conducted with support provided by the Biospecimen Procurement and Translational Pathol ogy and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). J.P, Borg' laboratory is funded by La Ligue Nationale Contre le Cancer (Label Ligue J.P. Borg), Fondation AMIDEX, and SIRIC (INCa-DGOS-Inserm 6038).

Publisher Copyright:
© 2018 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Erbin suppresses KSR1-mediated RaS/RAF signaling and tumorigenesis in colorectal cancer'. Together they form a unique fingerprint.

Cite this