The Levels of H11/HspB8 DNA Methylation in Human Melanoma Tissues and Xenografts Are a Critical Molecular Marker for 5-Aza-2′-Deoxycytidine Therapy

Abstract

H11/HspB8 is a functionally distinct small heat shock protein. It causes growth arrest in melanocytes, associated with the inhibition of Cyclin E/Cdk2 and β-catenin phosphorylation at the transcriptional activity site Ser⁵⁵² and is silenced through DNA methylation in 27/35 (77%) melanoma tissues/early cultures. 5-Aza-2′-deoxycytidine (Aza-C) induces melanoma cell death correlated with the levels of H11/HspB8 DNA methylation (p < .001). In line with low/moderate H11/HspB8 methylation, PI3-K inhibition increases Aza-C-induced cell death. Aza-C inhibits the growth of melanoma xenografts related to the levels of H11/HspB8 methylation, and a nonmethylated/non-TAK1 binding H11/HspB8 mutant confers Aza-C resistance. H11/HspB8 is a potential molecular marker for demethylation therapies.

Keywords: :

• Gene expression
• Molecular biology
• Cutaneous melanoma
• Therapy
• Prognosis and response predictions

ACKNOWLEDGMENTS

We thank Drs. G. Elias, J. W. Burnett, and J. Sinkovics for the gift of the melanoma cell suspensions and cultures. This research was supported by Public health Service grant AR053512 from NIAMS, National Institutes of Health (NIH).