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 dual‐specificity 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.

中文翻译：

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m6A 甲基转移酶 Wilms 的肿瘤 1 相关蛋白通过 m6A RNA 甲基化调节双特异性磷酸酶 6 的表达，促进 NK/T 细胞淋巴瘤的细胞增殖和顺铂耐药

鼻型自然杀伤/T细胞淋巴瘤（NKTCL）是一种侵袭性恶性肿瘤，其生存结果较差，对化疗相对耐药。N6-甲基腺苷 (m6A) 修饰是真核信使 RNA 最普遍的修饰，参与各种肿瘤的进展。然而，尚不清楚它是否在 NKTCL 发育中具有生理作用。为了解决这个问题，我们探讨了它在 NKTCL 中的功能和分子机制。最初，我们证明与正常 NK 细胞相比，Wilms 的肿瘤 1 相关蛋白 (WTAP)，一种主要的 RNA N6 腺苷甲基转移酶，在人 NKTCL 细胞系（YTS 和 SNK-6 细胞）中明显上调。在功能上，WTAP 的消耗显着抑制 YTS 和 SNK-6 细胞的增殖并促进细胞凋亡。而且，WTAP 的干预明显抑制了 NKTCL 细胞对顺铂的化疗耐药，这体现在 YTS 和 SNK-6 细胞中对细胞活力的抑制降低以及耐药相关蛋白表达 MRP-1 和 P-gp 的表达降低。关于机制，我们发现 WTAP 通过增加 DUSP6 mRNA 转录物的 m6A 水平来增强双特异性磷酸酶 6 (DUSP6) 的表达，从而导致 NKTCL 中的致癌功能。有趣的是，WTAP 通过以 m6A 依赖性方式稳定 DUSP6 mRNA，促进了 NKTCL 的进展和化疗敏感性。总之，这些发现揭示了 WTAP 引导的 m6A 甲基化的关键功能，并将 DUSP6 确定为 m6A 修饰在调节 NKTCL 肿瘤发生中化疗耐药性的重要靶标。