Oncogenic DNA methyltransferase 1 activates the PI3K/AKT/mTOR signalling by blocking the binding of HSPB8 and BAG3 in melanoma

Abnormal DNA methylation has been observed in multiple malignancies, including melanoma. In this study, we initially noticed the overexpression of DNA methyltransferase 1 (DNMT1) in melanoma samples in bioinformatics analysis and, subsequently, validated it in the purchased melanoma cell lines. After treatment with short-hairpin RNAs or Decitabine (a DNA methylation inhibitor), silencing of DNMT1 was demonstrated to suppress cell viability and invasive and migratory potentials as well as to augment apoptosis and autophagy in melanoma cells. To further explore the downstream mechanisms, we revealed that DNMT1 inhibited HSPB8 expression through augmenting HSPB8 methylation, thereby suppressing the binding between HSPB8 and BAG3. Then, we elucidated through a series of gain- and loss- of function assays that the interplay of HSPB8 and BAG3 blocked the PI3K/AKT/mTOR pathway, thereby repressing the malignant phenotypes of melanoma cells and contributing to melanoma cell apoptosis and autophagy. We further established a mouse model of melanoma and substantiated that DNMT1 enhanced the in vivo tumorigenesis of melanoma cells via activation of the PI3K/AKT/mTOR pathway through repressing the binding between HSPB8 and BAG3. Taken together, our data supported that DNMT1 repressed the binding between HSPB8 and BAG3 and activated the PI3K/AKT/mTOR pathway, thus playing a tumour-promoting role in melanoma.