Nuclear translocation of ATG5 induces DNA mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) via interacting with Mis18α in colorectal cancer
Nuclear translocation of ATG5 induces DNA mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) via interacting with Mis18α in colorectal cancer
复制标题
ATG5 的核易位通过与结直肠癌中的 Mis18α 相互作用诱导 DNA 错配修复缺陷 (MMR–D)/微卫星不稳定性 (MSI)
DOI：
10.1111/bph.15422
复制
发表时间：
2021-04-29
影响因子：
7.3
通讯作者：
Qu, Xian-Jun
中科院分区：
文献类型：
--
作者：
Sun, Shi-Yue;Hu, Xue-Tao;Qu, Xian-Jun
Background and Purpose It is well known that microsatellite instability-high (MSI-H) is associated with 5-fluorouracil (5-FU) resistance in colorectal cancer. MSI-H is the phenotype of DNA mismatch repair deficiency (MMR-D), mainly occurring due to hypermethylation of MLH1 promoter CpG island. However, the mechanisms of MMR-D/MSI-H are unclear. We aim to investigate the pathway of MMR-D/MSI-H involved in 5-FU resistance.Experimental Approach Human colorectal cancer specimens were diagnosed for MSI-H by immunohistochemistry and western blotting. Proteome microarray interactome assay was performed to screen nuclear proteins interacting with ATG5. Nuclear ATG5 and ATG5-Mis18 alpha overexpression were analysed in ATG5(high) colorectal cancer bearing mice. The methylation assay determined the hypermethylation of hMLH1 promoter CpG island in freshly isolated human colorectal cancer tissue samples and HT29(atg5) and SW480(atg5) cancer cells.Key Results In ATG5(high) colorectal cancer patients, 5-FU-based therapy resulted in nuclear translocation of ATG5, leading to MSI-H. Colorectal cancer in Atg5 Tg mice demonstrated 5-FU resistance, compared to Atg5(+/-) and WT mice. Proteome microarray assay identified Mis18 alpha, a protein localized on the centromere and a source for methylation of the underlying chromatin, which responded to the translocated nuclear ATG5 leading to ATG5-Mis18 alpha conjugate overexpression. This resulted in MLH1 deficiency due to hypermethylation of hMLH1 promoter CpG island, while the deletion of nuclear Mis18 alpha failed to induce ATG5-Mis18 alpha complex and MMR-D/MSI-H.Conclusions and Implications Nuclear ATG5 resulted in MMR-D/MSI-H through its interaction with Mis18 alpha in ATG5(high) colorectal cancer cells. We suggest that ATG5-Mis18 alpha or Mis18 alpha may be a therapeutic target for treating colorectal cancer.
