title: The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways.
abstract: CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kajiro
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hirota
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Kaori
authors.initials: K
authors.lastname: Kawanowa
authors.forename: Kae
authors.initials: K
authors.lastname: So-ma
authors.forename: Ichiaki
authors.initials: I
authors.lastname: Ito
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Sho-hei
authors.initials: SH
authors.lastname: Ohie
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Seino
authors.forename: Miwako
authors.initials: M
authors.lastname: Kawano
authors.forename: Yoh-ichi
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takei
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kurosumi
authors.forename: Akiko
authors.initials: A
authors.lastname: Murayama
authors.forename: Keiji
authors.initials: K
authors.lastname: Kimura
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D056921:Nuclear Receptor Coactivator 3; D011499:Protein Processing, Post-Translational; D015534:Trans-Activators / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases