| First Author | Sun SY | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 11 | Pages | 2351-2369 |
| PubMed ID | 33645631 | Mgi Jnum | J:347169 |
| Mgi Id | MGI:7616606 | Doi | 10.1111/bph.15422 |
| Citation | Sun SY, et al. (2021) Nuclear translocation of ATG5 induces DNA mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) via interacting with Mis18alpha in colorectal cancer. Br J Pharmacol 178(11):2351-2369 |
| abstractText | 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-Mis18alpha 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 Mis18alpha, 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-Mis18alpha conjugate overexpression. This resulted in MLH1 deficiency due to hypermethylation of hMLH1 promoter CpG island, while the deletion of nuclear Mis18alpha failed to induce ATG5-Mis18alpha complex and MMR-D/MSI-H. CONCLUSIONS AND IMPLICATIONS: Nuclear ATG5 resulted in MMR-D/MSI-H through its interaction with Mis18alpha in ATG5(high) colorectal cancer cells. We suggest that ATG5-Mis18alpha or Mis18alpha may be a therapeutic target for treating colorectal cancer. |
