AKAP12 Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity

• Published in: Oncogene Vol. 23; no. 42; pp. 7095 - 7103
• Main Authors: CHOI, Moon-Chang, JONG, Hyun-Soon, TAI YOUNG KIM, SONG, Sang-Hyun, DONG SOON LEE, JUNG WEON LEE, KIM, Tae-You, NOE KYEONG KIM, BANG, Yung-Jue
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 16.09.2004; Nature Publishing Group
• Subjects: A Kinase Anchor Proteins; Adrenergic receptors; Ageing, cell death; Apoptosis; Base Sequence; Biological and medical sciences; Bisulfite; Cancer research; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell death; Cell Division - genetics; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; CpG islands; DNA methylation; DNA methyltransferase; DNA Primers; Epigenetics; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gene silencing; Genes; Histone deacetylase; Histone methyltransferase; Humans; Internal medicine; Isoforms; Kinases; Medical research; Medical schools; Medicine; Mitogens - antagonists & inhibitors; Mitogens - genetics; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Transcription. Transcription factor. Splicing. Rna processing; Tumors; University colleges; Human; Growth; Transcription promoter; Malignant tumor; alternative promoter; Carcinogenesis; Mechanism; AKAP12; Deacetylation; DNA; Epigenetics; DNA methylation; Digestive diseases; histone deacetylation; Histone; Methylation; Gastric disease; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207932

AKAP12/Gravin, one of the A-kinase anchoring proteins (AKAPs), functions as a kinase scaffold protein and as a dynamic regulator of the beta2-adrenergic receptor complex. However, the biological role of AKAP12 in cancer development is not well understood. The AKAP12 gene encodes two major isoforms of 305 and 287 kDa (designated AKAP12A and AKAP12B, respectively, in this report). We found that these two isoforms are independently expressed and that they are probably under the control of two different promoters. Moreover, both isoforms were absent from the majority of human gastric cancer cells. The results from methylation-specific PCR (MSP) and bisulfite sequencing revealed that the 5' CpG islands of both AKAP12A and AKAP12B are frequently hypermethylated in gastric cancer cells. Treatment with DNA methyltransferase inhibitor and/or histone deacetylase inhibitor efficiently restored the expression of AKAP12 isoforms, confirming that DNA methylation is directly involved in the transcriptional silencing of AKAP12 in gastric cancer cells. Hypermethylation of AKAP12A CpG island was also detected in 56% (10 of 18) of primary gastric tumors. The restoration of AKAP12A in AKAP12-nonexpressing cells reduced colony formation and induced apoptotic cell death. In conclusion, our results suggest that AKAP12A may function as an important negative regulator of the survival pathway in human gastric cancer.