DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation.

Cellular apoptosis is a central mechanism leveraged by chemotherapy to treat human cancers. 5-Methylcytosine (m5C) modifications installed on both DNA and mRNA are documented to regulate apoptosis independently. However, the interplay or crosstalk between them in cellular apoptosis has not yet been explored. Here, we reported that promoter methylation by DNMT1 coordinated with mRNA methylation by NSun2 to regulate osteosarcoma cell apoptosis. DNMT1 was induced during osteosarcoma cell apoptosis triggered by chemotherapeutic drugs, whereas NSun2 expression was suppressed. DNMT1 was found to repress NSun2 expression by methylating the NSun2 promoter. Moreover, DNMT1 and NSun2 regulate the anti-apoptotic genes AXL, NOTCH2, and YAP1 through DNA and mRNA methylation, respectively. Upon exposure to cisplatin or doxorubicin, DNMT1 elevation drastically reduced the expression of these anti-apoptotic genes via enhanced promoter methylation coupled with NSun2 ablation-mediated attenuation of mRNA methylation, thus rendering osteosarcoma cells to apoptosis. Collectively, our findings establish crosstalk of importance between DNA and RNA cytosine methylations in determining osteosarcoma resistance to apoptosis during chemotherapy, shedding new light on future treatment of osteosarcoma, and adding additional layers to the control of gene expression at different epigenetic levels.