Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer

Seong Hye Park, Soyeon Jeong, Bo Ram Kim, Yoon A. Jeong, Jung Lim Kim, Yoo Jin Na, Min Jee Jo, Hye Kyeong Yun, Dae Yeong Kim, Bu Gyeom Kim, Dae Hee Lee, Sang Cheul Oh

Research output: Contribution to journalArticle

Abstract

Hypoxia, or the deficiency of oxygen, in solid tumors is majorly responsible for the progression of cancer and remains unaffected by chemotherapy, but still requires definitive definition of the hypoxia signaling. Hypoxia disrupts the complete folding of mitochondrial proteins, leading to several diseases. The present study confirms that hypoxia activates the Hedgehog pathway in colorectal cancer (CRC), considering its role in cancer epithelial to mesenchymal transition, migration, and invasion. The activity of hypoxia-mediated Gli-1, a Hedgehog signaling factor in hypoxia, was confirmed by in vitro western blotting, immunofluorescence staining, wound-healing assay, and matrigel invasion assay, as well as by in vivo xenograft models (n = 5 per group). The Gli-1 mechanism in hypoxia was analyzed via mass spectrometry. Hypoxia enhanced the interaction of Gli-1 and T-complex protein 1 subunit beta (CCT2), as observed in the mass spectrometric analysis. We observed that reduction in CCT2 inhibits tumor induction by Gli-1. Ubiquitination-mediated Gli-1 degradation by β-TrCP occurs during incomplete folding of Gli-1 in hypoxia. The human CRC tissues revealed greater CCT2 expression than did the normal colon tissues, indicating that higher CCT2 expression in tumor tissues from CRC patients reduced their survival rate. Moreover, we suggest that CCT2 correlates with Gli-1 expression and is an important determinant of survival in the CRC patients. The results reveal that CCT2 can regulate the folding of Gli-1 in relation to hypoxia in CRC.

Original languageEnglish
Pages (from-to)136-150
Number of pages15
JournalOncogene
Volume39
Issue number1
DOIs
Publication statusPublished - 2020 Jan 2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Park, S. H., Jeong, S., Kim, B. R., Jeong, Y. A., Kim, J. L., Na, Y. J., Jo, M. J., Yun, H. K., Kim, D. Y., Kim, B. G., Lee, D. H., & Oh, S. C. (2020). Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer. Oncogene, 39(1), 136-150. https://doi.org/10.1038/s41388-019-0972-6