The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways
The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways
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DOI：
10.1038/ncb1839
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发表时间：
2009-03-01
影响因子：
21.3
通讯作者：
Yanagisawa, Junn
中科院分区：
文献类型：
--
作者：
Kajiro, Masashi;Hirota, Ryuichi;Yanagisawa, Junn
CHIP是一种U盒型泛素连接酶，可诱导其底物的泛素化和降解，其中包括几种致癌蛋白（1-12）。然而，CHIP与肿瘤进展之间的关系尚未阐明。在这里，我们表明CHIP通过抑制致癌途径抑制人类乳腺癌的肿瘤进展。CHIP水平与人乳腺肿瘤组织的恶性程度呈负相关。在裸鼠异种移植模型中，CHIP表达显著抑制肿瘤生长和转移。相比之下，在乳腺癌细胞中敲低CHIP（shCHIP）导致小鼠肿瘤快速生长和肿瘤表型。在基于细胞的实验中，由于Bcl 2，Akt 1，Smad和Twist的表达增加，shCHIP细胞的锚定非依赖性生长和侵袭性显著升高。蛋白质组学分析确定转录共激活因子SRC-3（参考文献13 -19）是CHIP泛素化和降解的直接靶点。在shCHIP细胞中敲低SRC-3降低了Smad和Twist的表达，并抑制了体内肿瘤转移。相反，SRC-3共表达阻止了CHIP诱导的转移形成抑制。这些观察结果表明，CHIP通过降解致癌蛋白（包括SRC-3）抑制锚定非依赖性细胞生长和转移潜力。
CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins(1-12). 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 (refs13-19) 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.