Methyltransferase-like 3 enhances cell proliferation and cisplatin resistance in natural killer/T-cell lymphoma through promoting N6-methyladenosine modification and the stability of staphylococcal nuclease and Tudor domain-containing protein 1 mRNA.

Abstract

Nasal-type natural killer/T-cell lymphoma (NKTCL) is a typical class of non-Hodgkin's lymphoma, which is quite malignant because of its high resistance to chemotherapy. N6-methyladenosine (m6A) modification, a prevalent modification of eukaryotic RNA, was emerging as an important regulatory mechanism in progression of various tumors. Here, we demonstrated that methyltransferase-like 3 (METTL3), an RNA methyltransferase, was obviously upregulated in human NKTCL cell lines (NK-92, YTS, SNT-8, and SNK-6) compared with normal NK cells. Knockdown of METTL3 noticeably repressed proliferation and facilitated apoptosis in SNT-8 cells, whereas overexpression of METTL3 showed opposite results in SNK-6 cells. In the mechanism exploration, we found that METTL3 stimulated the m6A modification of staphylococcal nuclease and Tudor domain-containing protein 1 (SND1) mRNA, recruited YTH m6A RNA binding protein 1 to recognize the m6A site, thereby enhancing its mRNA stability. Rescue experiments demonstrated that METTL3 significantly prohibited NKTCL cell chemotherapy sensitivity to cisplatin (DDP) through regulating SND1 expression. Furthermore, knockdown of SND1 suppressed tumor growth and reduced DDP resistance in vivo . Taken together, our findings uncovered the role of METTL3 in the regulation of chemotherapy resistance in NKTCL oncogenesis.