Oncotarget

Research Papers:

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

Shin-Ai Lee, Han-Sae Lee, Shin-Kyoung Hur, Sang Won Kang, Goo Taeg Oh, Daekee Lee and Jongbum Kwon _

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Oncotarget. 2017; 8:115041-115053. https://doi.org/10.18632/oncotarget.22984

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Abstract

Shin-Ai Lee1,2, Han-Sae Lee1,2, Shin-Kyoung Hur1, Sang Won Kang1,2, Goo Taeg Oh1, Daekee Lee1 and Jongbum Kwon1,2

1Department of Life Science, Ewha Womans University, Seodaemun-gu, Seoul, 03760, Korea

2The Research Center for Cellular Homeostasis, Ewha Womans University, Seodaemun-gu, Seoul, 03760, Korea

Correspondence to:

Jongbum Kwon, email: jongkwon@ewha.ac.kr

Keywords: INO80 chromatin remodeling complex; colon cancer; APC Min mouse model; replication stress; apoptosis

Received: September 01, 2017     Accepted: November 17, 2017     Published: December 06, 2017

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 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.


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