AKAP12α is AssoCiated with Promoter Methylation in Lung Cancer

Abstract

P urpose: P romoter methylation is an important mechanism for silencing tumor-suppressor genes in cancer and it is a promising tool for the development of molecular biomarkers. The purpose of the present study was to investigate whether inactivation of the A Kinase Anchoring P rotein 12 (AKAP 12) gene is associated with promoter methylation in lung cancer.M aterials and M ethods: The AKAP 12 expression was examined by reverse transcription-polymerase chain reaction (R T-P C R ) in ten lung cancer cell lines. The methylation status of the AKAP 12α promoter was analyzed by performing bisulfite sequencing analysis in ten lung cancer cell lines, twenty four lung tissues and matched normal tissues.R esults: The AKAP 12α expression was reduced in 6 of 10 (60% ) lung cancer cell lines, whereas the AKAP 12β expression was absent in 1 of 10 (10% ) lung cancer cell lines. The AKAP 12α expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in three lung cancer cell lines.M ethylation of C pG island 1 in the AKAP 12α promoter was detected in 30% of the lung cancer cell lines, whereas methylation of C pG island 2 in the AKAP 12α promoter was observed in the immortalized bronchial cell line and in all the lung cancer cell lines. In lung tumors, the C pG island 1 in the AKAP 12α promoter was infrequently methylated. H owever, C pG island 2 in the AKAP 12α promoter was highly methylated in lung tumors compared with the surrounding normal tissues, and this was statistically significant (p=0.0001).

The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells

“…This is consistent with other studies showing that AKAP12 expression is associated with epigenetic modifications such as promoter hypermethylation [27][28][29][30]. However, the removal of HDAC7 is only a prerequisite for the transcriptional machinery to induce the gene expression.…”

Emerging Roles for SSeCKS/Gravin/AKAP12 in the Control of Cell Proliferation, Cancer Malignancy, and Barriergenesis

“…In silico analyses at the Cancer Genome Anatomy Project SAGE (Serial Analysis of Gene Expression) site (http://cgap.nci.nih.gov/SAGE) identify AKAP12 downregulation in human thyroid, lung and liver cancer tissue, in human ovarian cancer cell lines. The majority of cancers suffering from epigenetic AKAP12 silencing seem to be regulated via promoter hypermethylation (70, 78, 85, 88, 99, 100), although instances exist where AKAP12 silencing is through changes in histone acetylation (78). Indeed, the silencing of AKAP12 via promoter hypermethylation (101, 102) has been shown to function as a neoplastic progression biomarker in Barrett’s esophagus (103).…”

Retinoid-Induced Expression and Activity of an Immediate Early Tumor Suppressor Gene in Vascular Smooth Muscle Cells

“…AKAP12 (aka SSeCKS and Gravin) has demonstrable growth suppressive properties and is down-regulated in a variety of human neoplasms supporting the idea that AKAP12 is a bonafide tumor suppressor gene [32], [34], [36]–[40]. However, there is little information on the role of AKAP12 in non-neoplastic cell growth inhibition.…”

“…Initial studies demonstrated the importance of serum response factor-binding CArG boxes in the regulation of Akap12α promoter activity [48]. Adjacent GC-rich sequences in the Akap12α promoter were shown to undergo hypermethylation and gene silencing in various cancer cell lines; in contrast, the Akap12β promoter exhibited less gene silencing in cancer cells [34], [39], [40]. A subsequent study demonstrated a methylation-independent mechanism for Akap12α promoter silencing through the recruitment of HDAC1 [49].…”