RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

F. C. Lin; Y. P. Liu; C. H. Lai; Y. S. Shan; H. C. Cheng; P. I. Hsu; C. H. Lee; Y. C. Lee; H. Y. Wang; C. H. Wang; J. Q. Cheng; M. Hsiao; P. J. Lu

doi:10.1038/onc.2011.596

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

F. C. Lin, Y. P. Liu, C. H. Lai, Y. S. Shan, H. C. Cheng, P. I. Hsu, C. H. Lee, Y. C. Lee, H. Y. Wang, C. H. Wang, J. Q. Cheng, M. Hsiao, P. J. Lu

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

Abstract

Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.

Original language	English
Pages (from-to)	4302-4316
Number of pages	15
Journal	Oncogene
Volume	31
Issue number	39
DOIs	https://doi.org/10.1038/onc.2011.596
Publication status	Published - Sept 27 2012
Externally published	Yes

Keywords

β-catenin
Akt
cyclin D1
gastric cancer
RUNX3

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/onc.2011.596

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title = "RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells",

abstract = "Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.",

keywords = "β-catenin, Akt, cyclin D1, gastric cancer, RUNX3",

author = "Lin, {F. C.} and Liu, {Y. P.} and Lai, {C. H.} and Shan, {Y. S.} and Cheng, {H. C.} and Hsu, {P. I.} and Lee, {C. H.} and Lee, {Y. C.} and Wang, {H. Y.} and Wang, {C. H.} and Cheng, {J. Q.} and M. Hsiao and Lu, {P. J.}",

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AU - Lin, F. C.

AU - Liu, Y. P.

AU - Lai, C. H.

AU - Shan, Y. S.

AU - Cheng, H. C.

AU - Hsu, P. I.

AU - Lee, C. H.

AU - Lee, Y. C.

AU - Wang, H. Y.

AU - Wang, C. H.

AU - Cheng, J. Q.

AU - Hsiao, M.

AU - Lu, P. J.

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N2 - Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.

AB - Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.

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KW - Akt

KW - cyclin D1

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KW - RUNX3

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RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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