The m6A methyltransferase METTL3 modifies Kcnk6 promoting on inflammation associated carcinogenesis is essential for colon homeostasis and defense system through histone lactylation dependent YTHDF2 binding

Inflammation induces tumor formation and plays a crucial role in tumor progression and prognosis. KCNK6, by regulating K(+) efflux to reduce NLRP3 Inflammasome-induced lung injury, relaxes the aorta. This study aims to elucidate the effects and biological mechanism of KCNK6 in inflammation-associated carcinogenesis, which may be essential for colon homeostasis and the defense system. To induce colitis, mice were given 3.0% Dextran Sodium Sulfate (DSS) in their drinking water for 7 days. The Azoxymethane (AOM) +DSS method was used to induce colon cancer in the mice model. Bone marrow-derived macrophages (BMDM) from Kcnk6-/- mice, AW264.7 cells, and human colon cancer HCT116 and Caco2 cells were used as <i>in vitro</i> models. The loss of Kcnk6 prevented spontaneous colitis and restored mucosal integrity and homeostatic molecules. Additionally, the loss of Kcnk6 reduced the severity of AOM/DSS-induced carcinogenesis. Kcnk6 promoted cell viability and proliferation in HCT-116 or Caco-2 cells. The loss of Kcnk6 inhibited the levels of inflammatory factors in BMDM cells. Kcnk6 accelerated potassium channel activity, inducing NLRP3 inflammasome activation. METTL3-mediated m6A modification increased Kcnk6 stability in a YTHDF2-dependent manner. Histone lactylation activated the transcription of YTHDF2/Kcnk6. Our study revealed the important role of Kcnk6 in inflammation-associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in a YTHDF2-dependent manner, providing a potential strategy for inflammation-associated carcinogenesis or colorectal cancer therapy. Our study revealed the important role of Kcnk6 senescence in inflammation associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in YTHDF2- dependent manner, providing a potential strategy for inflammation associated carcinogenesis or colorectal cancer therapy.

炎症可诱导肿瘤发生，并在肿瘤进展与预后过程中发挥关键作用。KCNK6可通过调控K⁺外流，减轻NLRP3炎症小体（NLRP3 Inflammasome）介导的肺损伤，并舒张主动脉。本研究旨在阐明KCNK6在炎症相关癌变中的作用及生物学机制，该机制或对结肠稳态与机体防御系统至关重要。为构建结肠炎模型，实验小鼠饮用添加3.0%葡聚糖硫酸钠（Dextran Sodium Sulfate，DSS）的饮水，持续7天。本研究采用偶氮甲烷（Azoxymethane，AOM）联合DSS的方案，构建小鼠结肠癌模型。实验采用Kcnk6基因敲除（Kcnk6⁻/⁻）小鼠的骨髓源性巨噬细胞（Bone marrow-derived macrophages，BMDM）、AW264.7细胞，以及人结肠癌细胞HCT116与Caco2细胞作为体外（in vitro）模型。敲除Kcnk6可抑制自发性结肠炎的发生，修复黏膜完整性，并恢复稳态相关分子的表达水平。此外，敲除Kcnk6可减轻AOM/DSS诱导的癌变进程严重程度。KCNK6可增强HCT-116及Caco-2细胞的细胞活力与增殖能力。敲除Kcnk6可抑制BMDM细胞中炎症因子的表达水平。KCNK6可增强钾通道活性，进而诱导NLRP3炎症小体活化。甲基转移酶样蛋白3（METTL3）介导的N⁶-甲基腺嘌呤（m⁶A）修饰，可通过YTH结构域结合蛋白2（YTHDF2）依赖的途径提升Kcnk6的稳定性。组蛋白乳酸化可激活YTHDF2与Kcnk6的转录。本研究揭示了KCNK6在炎症相关癌变进程中的重要作用。作为m⁶A甲基转移酶的METTL3与组蛋白乳酸化，可通过YTHDF2依赖的方式提升Kcnk6的稳定性，为炎症相关癌变或结直肠癌的治疗提供了潜在策略。本研究同时揭示了KCNK6衰老在炎症相关癌变进程中的重要作用，METTL3与组蛋白乳酸化可通过YTHDF2依赖的方式提升Kcnk6的稳定性，为炎症相关癌变或结直肠癌的治疗提供了潜在策略。