<p>A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of <i>AKAP12</i> has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three <i>AKAP12</i> promoters (i.e., α, β, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The <i>AKAP12</i>α promoter shows DNA hypermethylation in JMML samples, which is associated with decreased <i>AKAP12</i>α expression. Promoter methylation of <i>AKAP12</i>α correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. <i>In silico</i> screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the <i>AKAP12</i>α promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of <i>AKAP12</i> promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the <i>AKAP12</i> promoter in JMML. Exposure to DNMT- and HDAC-inhibitors reactivates <i>AKAP12</i>α expression <i>in vitro</i>, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of <i>AKAP12</i>α in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.</p
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