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, Jongbum Kwon

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Pages (from-to)115041-115053
Number of pages13
JournalOncotarget
Volume8
Issue number70
DOIs
StatePublished - 2017

Keywords

  • APC Min mouse model
  • Apoptosis
  • Colon cancer
  • INO80 chromatin remodeling complex
  • Replication stress

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