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

Cited 76 time in Web of Science Cited 78 time in Scopus
Authors
Choi, Moon-Chang; Jong, Hyun-Soon; Kim, Tai Young; Song, Sang-Hyun; Lee, Dong Soon; Lee, Jung Weon; Kim, Tae-You; Kim, Noe-Kyeong; Bang, Yung-Jue
Issue Date
2004-09
Citation
Oncogene, Vol.23 No.42, pp.7095-7103
Keywords
AKAP12alternative promoterDNA methylationhistone deacetylationapoptosis
Abstract
AKAP12/Gravin, one of the A-kinase anchoring proteins (AKAPs), functions as a kinase scaffold protein and as a dynamic regulator of the beta(2)-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.
ISSN
0950-9232
URI
https://hdl.handle.net/10371/173199
DOI
https://doi.org/10.1038/sj.onc.1207932
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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