Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1.
The tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) was frequently mutated in cancers. The modulation mechanism of ARID1A for PI3K/AKT signaling in gastric cancer (GC) remains elusive. Here, we found that depletion of endogenous ARID1A enhanced the in vitro proliferation, colony formation, cellular growth, nutrient uptake and in vivo xenograft tumor growth of GC cells. PI3K/AKT activation by ARID1A-silencing was profiled using a phospho-protein antibody array. The phosphorylation of PDK1, AKT, GSK3β and 70S6K, and the protein and mRNA expressions of PI3K and PDK1, were upregulated by ARID1A-silencing. Chromatin immunoprecipitation and luciferase reporter assay revealed that ARID1A-involved SWI/SNF complex inhibited PIK3CA and PDK1 transcription by direct binding to their promoters. Serial deletion mutation analyses revealed that the ARID1A central region containing the HIC1-binding domain, but not the ARID DNA-binding domain and the C-terminal domain, was essential for the inhibition of GC cell growth, PI3K/AKT pathway phosphorylation and its transcriptional modulation activity of PIK3CA and PDK1. The proliferation, cellular growth and glucose consumption of ARID1A-deficient GC cells were efficiently prohibited by allosteric inhibitors mk2206 and LY294002, which targeting AKT and PI3K, respectively. Both inhibitors also downregulated the phosphorylation of PI3K/AKT pathway in ARID1A-deficient GC cells. Such cells were sensitized to the treatment of LY294002, and AT7867, another inhibitor of AKT and p70S6K. The administration of LY294002 alone inhibited the in vivo growth of ARID1A- deficient GC cells in mouse xenograft model. Our study provides a novel insight into the modulatory function and mechanism of ARID1A in PI3K/AKT signaling in GC.
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Qian
Q
Zhang
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Hai-Bo
HB
Yan
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Jie
J
Wang
College of Bioscience and Biotechnology, Key Laboratory of Crop Genetics and Physiology of Jiangsu Province, Yangzhou University, Yangzhou 225009, China.
Shu-Jian
SJ
Cui
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Xiao-Qing
XQ
Wang
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Ying-Hua
YH
Jiang
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.
Li
L
Feng
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.|Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Peng-Yuan
PY
Yang
Minhang Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201199, China.|Department of Chemistry, Fudan University, Shanghai 200433, China.
Feng
F
Liu
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*
C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014157:Transcription Factors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D017346:Protein Serine-Threonine Kinases
ARID1A; PDK1; PIK3CA; SWI/SNF complex; gastric cancer