Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation.
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.
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.|Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Song-Hui
SH
Xu
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.|Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Jin-Zhou
JZ
Huang
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.|Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Min
M
Chen
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.|Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Ming
M
Zeng
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.
Fei-Yan
FY
Zou
Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
De
Chen
Institutes of Life and Health Engineering, Jinan University, Guangzhou, China.|Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
Guang-Rong
GR
Yan
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
D002352:Carrier Proteins; C513410:ECD protein, human; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human
ACK1; amplification; gastric cancer; p53