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INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis
- INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis
- Lee S.-A.; Lee H.-S.; Hur S.-K.; Kang S.W.; Oh G.T.; Lee D.; Kwon J.
- Ewha Authors
- 강상원; 권종범; 오구택; 이대기; 이한새
- SCOPUS Author ID
- 강상원; 권종범; 오구택; 이대기
- Issue Date
- Journal Title
- Oncotarget vol. 8, no. 70, pp. 115041 - 115053
- APC Min mouse model; Apoptosis; Colon cancer; INO80 chromatin remodeling complex; Replication stress
- Impact Journals LLC
- SCIE; SCOPUS
- Document Type
- The INO80 chromatin-remodeling complex performs functions in many chromosomal processes that are crucial for genome stability, such as DNA replication and stalled replication fork recovery. Although these functions suggest that INO80 acts as a tumor suppressor, its specific role in tumorigenesis has remained obscure. Here, we show that a haploinsufficient mutation of Ino80, the catalytic ATPase of the INO80 complex, decreased intestinal adenomatous polyps and increased survival in an Apcmin/+ mouse model of colon cancer. Experiments using tumors obtained from Apcmin/+ mice and cells from human colon cancers showed that this Ino80 defect induced stalled replication forks, the concomitant activation of ATR-Chk1 signaling and an increase in apoptosis, suggesting that Ino80 haploinsufficiency inhibited colon cancer tumorigenesis by activating replication stress-induced ATR-Chk1 signaling to increase apoptosis. Importantly, in human colon cancer, we observed that the INO80 subunits were frequently present in high copy numbers and exhibited a high rate of amplification and increased protein expression. These results show that in contrast to our original prediction that INO80 acts as a tumor suppressor, INO80 actually functions oncogenically to promote colon tumorigenesis. INO80 therefore represents a novel therapeutic target in colon cancer. The results of this study also reinforce the emerging notion that while genomic instability can promote tumorigenesis, in certain genetic contexts, it can also act as a tumor suppressor. © Lee et al.
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