IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line.
IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line.
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DOI：
10.18632/oncotarget.26049
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发表时间：
2018-09-21
期刊：
影响因子：
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通讯作者：
Takahashi SI
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文献类型：
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作者：
Furuta H;Yoshihara H;Fukushima T;Yoneyama Y;Ito A;Worrall C;Girnita A;Girnita L;Yoshida M;Asano T;Komada M;Kataoka N;Chida K;Hakuno F;Takahashi SI
胰岛素样生长因子（IGF）已被证明可以诱导多种类型细胞的增殖。胰岛素受体底物 (IRS) 是 IGF-I 受体 (IGF-IR) 酪氨酸激酶 (IGF-IR) 激活的主要靶标，已知在下游信号通路（例如 Erk1/2 通路）的激活中发挥重要作用。 IGF 信号传导失调代表了人类致癌过程中的一个核心肿瘤促进原理。前列腺癌高度依赖于 IGF/IGF-IR/IRS 轴。在这里，我们确定了去泛素酶、泛素特异性肽酶 9X (USP9X) 作为 IRS-2 的新型结合伴侣。在人前列腺癌细胞系中，小干扰 RNA (siRNA) 介导的 USP9X 敲除降低了 IGF-IR 和 IRS-2 蛋白水平，并增加了它们的泛素化。 USP9X 的敲低抑制了 Erk1/2 通路的基础激活，而 IRS-2 的外源表达可显着恢复这种激活，但 IGF-IR 则不能，这表明 USP9X 对 IRS-2 的稳定对于基础 Erk1/2 激活至关重要。最后，我们通过软琼脂集落形成测定测量了不依赖贴壁的细胞生长，这是一种典型的癌症特征。 USP9X 的敲低显着降低了前列腺癌细胞系的贴壁依赖性细胞生长。总而言之，我们的研究结果表明，USP9X 通过稳定 IRS-2 来维持 Erk1/2 通路的激活，从而促进前列腺癌的生长。
Insulin-like growth factors (IGFs) have been shown to induce proliferation of many types of cells. Insulin receptor substrates (IRSs) are major targets of IGF-I receptor (IGF-IR) tyrosine kinase activated by IGFs, and are known to play important roles in the activation of downstream signaling pathways, such as the Erk1/2 pathway. Dysregulation of IGF signaling represents a central tumor promoting principle in human carcinogenesis. Prostate carcinoma is highly dependent on the IGF/IGF-IR/IRS axis. Here we identified the deubiquitinase, ubiquitin specific peptidase 9X (USP9X) as a novel binding partner of IRS-2. In a human prostate carcinoma cell line, small interfering RNA (siRNA)-mediated knockdown of USP9X reduced IGF-IR as well as IRS-2 protein levels and increased their ubiquitination. Knockdown of USP9X suppressed basal activation of the Erk1/2 pathway, which was significantly restored by exogenous expression of IRS-2 but not by IGF-IR, suggesting that the stabilization of IRS-2 by USP9X is critical for basal Erk1/2 activation. Finally, we measured anchorage-independent cell growth, a characteristic cancer feature, by soft-agar colony formation assay. Knockdown of USP9X significantly reduced anchorage-independent cell growth of prostate carcinoma cell line. Taken all together, our findings indicate that USP9X is required for the promotion of prostate cancer growth by maintaining the activation of the Erk1/2 pathway through IRS-2 stabilization.