m6A methyltransferase Wilms' tumor 1‐associated protein facilitates cell proliferation and cisplatin resistance in NK/T cell lymphoma by regulating dual‐specificity phosphatases 6 expression via m6A RNA methylation

Abstract

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA, is involved in the progression of various tumors. However, it is unclear whether it has a physiological role in NKTCL development. To address this question, we probed its function and molecular mechanisms in NKTCL. Initially, we demonstrated that Wilms' tumor 1-associated protein (WTAP), a major RNA N6-adenosine methyltransferase, was obviously upregulated in human NKTCL cell lines (YTS and SNK-6 cells), compared with normal NK cells. Functionally, depletion of WTAP noticeably repressed proliferation and facilitated apoptosis in YTS and SNK-6 cells. Moreover, intervention of WTAP evidently prohibited NKTCL cell chemotherapy resistance to cisplatin, as reflected by a lower inhibition of cell viability and decreased expression of drug resistance-associated protein expression MRP-1 and P-gp in YTS and SNK-6 cells. With regard to the mechanism, we revealed that WTAP enhanced dualspecificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. Interestingly, WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. This study highlights WTAP as a potential therapeutic target of NKTCL treatment.

RNA N6‐methyladenosine modification in the lethal teamwork of cancer stem cells and the tumor immune microenvironment: Current landscape and therapeutic potential

“…This remarkable emerging technology provides a solid foundation for the clinical targeting of m 6 A modification in cancer treatment. Furthermore, some preclinical research also found that depletion of some m 6 A regulators can sensitize tumor cells to chemotherapies, including breast cancer and NK/T cell lymphoma 132,133 . Nevertheless, further detailed studies are required to realize its potential.…”

“…Furthermore, some preclinical research also found that depletion of some m 6 A regulators can sensitize tumor cells to chemotherapies, including breast cancer and NK/T cell lymphoma. 132,133 Nevertheless, further detailed studies are required to realize its potential. Finally, it is notable that m 6 A expression profiles have great potential to differentiate the immune characteristics of patients with tumors, which is likely to accurately guide the application of immunotherapy in clinical.…”

Insights into N6-methyladenosine and programmed cell death in cancer

“…WTAP, another MTC component, protects natural killer/T-cell lymphoma (NKTCL) cells from Bax-modulated apoptosis induced by cisplatin (DDP) via regulation of dual-specificity phosphatases 6 (DUSP6). That is, ablation of WTAP augmented the chemosensitivity of NKTCL by decreasing the drug resistance-associated proteins MRP1 and P-gp [ 131 ]. Saikosaponin-d (SsD), an FTO inhibitor, improved the efficacy of nilotinib and PKC412 by reducing FTO-mediated m 6 A hypomethylation and Bcl-2 transcripts in AML-resistant patients [ 137 ].…”

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

“…In addition to METTL3, WTAP has also been associated with cisplatin resistance. In nasal-type natural killer/T-cell lymphoma (NKTCL), WTAP contributes to cancer progression and chemotherapy sensitivity by stabilizing DUSP6 mRNA in an m6A-dependent manner [ 95 ]. In addition to cisplatin, oxaliplatin is a novel platinum drug that is used to circumvent cisplatin-mediated resistance mechanisms.…”