Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation

Song-Hui Xu; Jin-Zhou Huang; Min Chen; Ming Zeng; Fei-Yan Zou; De Chen; Guang-Rong Yan

doi:10.18632/oncotarget.6194

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Research Papers:

Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation

Song-Hui Xu, Jin-Zhou Huang, Min Chen, Ming Zeng, Fei-Yan Zou, De Chen and Guang-Rong Yan _

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Oncotarget. 2017; 8:12705-12716. https://doi.org/10.18632/oncotarget.6194

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Abstract

Song-Hui Xu1,2,*, Jin-Zhou Huang1,2,*, Min Chen1,2,*, Ming Zeng1,2,*, Fei-Yan Zou1, De Chen2,3, Guang-Rong Yan1,2,3

1Institutes of Life and Health Engineering, Jinan University, Guangzhou, China

2Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medicine University, Guangzhou, China

3Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China

*These authors have contributed equally to this work

Correspondence to:

Guang-Rong Yan, email: [email protected]

De Chen, email: [email protected]

Keywords: ACK1, gastric cancer, amplification, p53

Abbreviations: ACK1: activated Cdc42-associated kinase 1; ECD: ecdysoneless homolog; GC: gastric cancer; EMT: epithelial-mesenchymal transition

Received: July 30, 2015 Accepted: October 09, 2015 Published: October 20, 2015

ABSTRACT

Amplification or over-expression of an activated Cdc42-associated kinase 1 (ACK1) gene is common in breast, lung and ovarian cancers. However, little is known about the role of ACK1 in gastric tumorigenesis. Here, we found that DNA copy numbers of the ACK1 gene and its mRNA expression levels were significantly increased in gastric cancer (GC) compared to normal gastric tissues. Additionally, silencing ACK1 inhibited GC cell proliferation and colony formation, induced G2/M arrest and cellular apoptosis in vitro, and suppressed tumor growth in vivo. Gene Ontology annotation revealed that 147 differential proteins regulated by ACK1 knockdown were closely related with cellular survival. A cell cycle regulator, ecdysoneless homolog (ECD), was found to be significantly down-regulated by ACK1 knockdown. Silencing of ECD inhibited colony formation and induced G2/M arrest and cell apoptosis, which is similar to the effects of ACK1 knockdown. Silencing of ECD did not further enhance the effects of ACK1 knockdown on G2/M arrest and apoptosis, while silencing of ECD blocked the enhancement of colony formation by ACK1 over-expression. Over-expression of ACK or ECD promoted the ubiquitination of tumor suppressor p53 protein and decreased p53 levels, while silencing of ACK1 or ECD decreased the p53 ubiquitination level and increased p53 levels. Silencing of ECD attenuated the ubiquitination enhancement of p53 induced by ACK1 over-expression. Collectively, we demonstrate that amplification of ACK1 promotes gastric tumorigenesis by inducing an ECD-dependent ubiquitination degradation of p53.

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Research Papers:

Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation

Abstract