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INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis

Title
INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis
Authors
Lee, Shin-AiLee, Han-SaeHur, Shin-KyoungKang, Sang WonOh, Goo TaegLee, DaekeeKwon, Jongbum
Ewha Authors
강상원권종범오구택이대기이한새
SCOPUS Author ID
강상원scopus; 권종범scopus; 오구택scopus; 이대기scopus; 이한새scopus
Issue Date
2017
Journal Title
ONCOTARGET
ISSN
1949-2553JCR Link
Citation
ONCOTARGET vol. 8, no. 70, pp. 115041 - 115053
Keywords
INO80 chromatin remodeling complexcolon cancerAPC Min mouse modelreplication stressapoptosis
Publisher
IMPACT JOURNALS LLC
Indexed
SCOPUS WOS scopus
Document Type
Article
Abstract
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 Apc(min/+) mouse model of colon cancer. Experiments using tumors obtained from Apc(min/+) 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.
DOI
10.18632/oncotarget.22984
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자연과학대학 > 생명과학전공 > Journal papers
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