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.

miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression

“…(3) Several groups have reported that Runx2 protein stability is controlled through a ubiquitinproteasome-mediated protein degradation mechanism by Smurf1, (4) Schnurr-3 (Shn3)/WWP1, (5) and CHIP. (6) CHIP/STUB1 is a cochaperone protein identified through its interaction with Hsc/Hsp70, (7) and promotes the ubiquitination and degradation of chaperone-bound proteins, including receptor tyrosine kinase ErbB2, glucocorticoid receptor, (8) SCR-3, (9) Smads, and the mis-folded cystic fibrosis transmembrane conductance regulator protein. (10) Previously, we found that CHIP negatively regulates osteoblast differentiation by mediating degradation of Runx2.…”

Chaperone-assisted degradation: multiple paths to destruction

“…Moreover, recent studies demonstrate that an impairment of chaperone-assisted degradation causes diverse diseases and age-related pathologies (Zhang and Cuervo, 2008;Kajiro et al, 2009;Selcen et al, 2009). The 'degrading' activity of certain chaperones apparently fulfills an essential function within the proteostasis network.…”

Prognostic value of the ubiquitin ligase carboxyl terminus of the Hsc70‐interacting protein in postmenopausal breast cancer

“…We previously reported that the expression levels of CHIP mRNA were lower in breast cancer tissue than in normal breast tissue. Furthermore, immunohistochemical staining indicated that the expression levels of CHIP proteins were also lower in breast cancer cells 4. However, the mechanisms underlying the down‐regulated expression of CHIP in breast cancer currently remain unknown.…”

“…CHIP has been shown to suppress the expression of other oncogenic proteins that enhance anchorage‐independent tumor growth and metastatic potential in breast tumors. Our previous findings indicated that the down‐regulated expression of CHIP led to the accumulation of SRC‐3, thereby resulting in enhanced tumor migration and invasion through increases in Smad and Twist gene transcription 4, 5. Smad and Twist have recently been shown to favor the metastatic dissemination of cancer cells through their abilities to induce epithelial–mesenchymal transition 6, 7.…”