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The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways


CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins1,2,3,4,5,6,7,8,9,10,11,12. 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.

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Figure 1: Decreased CHIP expression in malignant breast tumour tissues.
Figure 2: CHIP suppresses tumour growth in a mouse xenograft model.
Figure 3: Downregulation of CHIP expression results in the malignant transformation of MCF-7 cells.
Figure 4: CHIP targets SRC-3 for ubiquitylation and degradation.
Figure 5: SRC-3 is the downstream regulator of CHIP during cancer metastasis.

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This work was supported by a nuclear system to decipher operation code (DECODE) and Targeted Proteins Research Program (TPRP) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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M. Kajiro. and R.H. performed most of the experiments; K.K., Y.Y., Y.K., Y.S., H.T., S. H. and M. Kurosumi. analysed human tissue samples; Y.N., K.S., I.I., S.O. and M. Kawano contributed to the animal experiments; K.K. and J.Y. planned the project.

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Correspondence to Junn Yanagisawa.

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The authors declare no competing financial interests.

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Kajiro, M., Hirota, R., Nakajima, Y. et al. The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol 11, 312–319 (2009).

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