Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
Mol Oncol. 2023 Feb;17(2):344-364. doi: 10.1002/1878-0261.13366. Epub 2022 Dec 30.
Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m A RNA modification plays critical role in many biological processes. However, the role of m A modification in CRC remains unclear. Here, we find that the m A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) expression, probably due to m A modification of METTL3 mRNA, followed by m A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3.
结直肠癌（CRC）是最常见的恶性肿瘤之一，CRC 死亡的主要原因是肿瘤转移。m6A RNA 修饰在许多生物学过程中发挥着关键作用。然而，m6A 修饰在 CRC 中的作用尚不清楚。在这里，我们发现 m6A 去甲基酶 alkB 同源物 1，组蛋白 H2A 双加氧酶（ALKBH1）在 CRC 中过表达，与转移和预后不良有关。ALKBH1 表达的上调促进了 CRC 的体外和体内转移。在机制上，ALKBH1 的敲低导致甲基转移酶 3、N6-腺苷-甲基转移酶复合物催化亚基（METTL3）表达减少，可能是由于 METTL3 mRNA 的 m6A 修饰，随后 SMAD 家族成员 7（SMAD7）mRNA 的 m6A 去甲基化。此外，SMAD7 的下调建立了侵袭性表型。更重要的是，通过沉默 SMAD7，ALKBH1 耗竭或 METTL3 耗竭引起的细胞迁移和侵袭缺陷显著逆转。综合这些结果，我们提出 ALKBH1 通过 METTL3 稳定 SMAD7 促进 CRC 转移。
