METTL16-mediated N6-methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer,Cell Proliferation

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METTL16-mediated N6-methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer
Cell Proliferation ( IF 5.9 ) Pub Date : 2023-12-12 , DOI: 10.1111/cpr.13590
Jimin Li ₁ , Fang Yang ₂ , Zeyu Wang ₃ , Siqing Zheng ₄ , Shuang Zhang ₁ , Chen Wang ₁ , Bing He ₁ , Jia-Bei Wang ₅ , Hao Wang ₁

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N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian messenger RNAs and is associated with numerous biological processes. However, its role in chromosomal instability remains to be established. Here, we report that an RNA m6A methyltransferase, METTL16, plays an indispensable role in the progression of chromosome segregation and is required to preserve chromosome stability in colorectal cancer (CRC) cells. Depletion or inhibition of the methyltransferase activity of METTL16 results in abnormal kinetochore-microtubule attachment during mitosis, leading to delayed mitosis, lagging chromosomes, chromosome mis-segregation and chromosomal instability. Mechanistically, METTL16 exerts its oncogenic effects by enhancing the expression of suppressor of glucose by autophagy 1 (Soga1) in an m6A-dependent manner. CDK1 phosphorylates Soga1, thereby triggering its direct interaction with the polo box domain of PLK1. This interaction facilitates PLK1 activation and promotes mitotic progression. Therefore, targeting the METTL16-Soga1 pathway may provide a potential treatment strategy against CRC because of its essential role in maintaining chromosomal stability.

中文翻译：

METTL16介导的Soga1 N6-甲基腺苷修饰能够在结直肠癌中实现适当的染色体分离和染色体稳定性

N6-甲基腺苷 (m6A) 是哺乳动物信使 RNA 中最常见的内部修饰，与许多生物过程相关。然而，它在染色体不稳定中的作用仍有待确定。在这里，我们报道了一种 RNA m6A 甲基转移酶 METTL16，在染色体分离的过程中发挥着不可或缺的作用，并且是维持结直肠癌 (CRC) 细胞染色体稳定性所必需的。 METTL16甲基转移酶活性的耗竭或抑制会导致有丝分裂期间着丝粒-微管附着异常，从而导致有丝分裂延迟、染色体滞后、染色体错误分离和染色体不稳定。从机制上讲，METTL16 通过以 m6A 依赖性方式增强自噬 1 ( Soga1 ) 葡萄糖抑制因子的表达来发挥其致癌作用。 CDK1 磷酸化 Soga1，从而触发其与 PLK1 的 polo box 结构域的直接相互作用。这种相互作用促进 PLK1 激活并促进有丝分裂进展。因此，由于 METTL16-Soga1 通路在维持染色体稳定性方面发挥着重要作用，因此针对 CRC 可能提供一种潜在的治疗策略。

更新日期：2023-12-12

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