CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer

Yangmeng Wang, Fangli Ren, Yinyin Wang, Yarui Feng, Dianjun Wang, Baoqing Jia, Ying Qiu, Shiyan Wang, Jun Yu, Joseph JY Sung, Jiake Xu, Nikolajs Zeps, Zhijie Chang

Research output: Contribution to journalArticleResearchpeer-review

56 Citations (Scopus)

Abstract

The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1a, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.

Original languageEnglish
Pages (from-to)983-991
Number of pages9
JournalCarcinogenesis
Volume35
Issue number5
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Cite this