title: CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer.
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 1α, 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.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Yangmeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Fangli
authors.initials: F
authors.lastname: Ren
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Wang
authors.forename: Yarui
authors.initials: Y
authors.lastname: Feng
authors.forename: Dianjun
authors.initials: D
authors.lastname: Wang
authors.forename: Baoqing
authors.initials: B
authors.lastname: Jia
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiu
authors.forename: Shiyan
authors.initials: S
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph Jy
authors.initials: JJ
authors.lastname: Sung
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Zeps
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases