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.