Research Papers:

IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line

Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yosuke Yoneyama, Akihiro Ito, Claire Worrall, Ada Girnita, Leonard Girnita, Minoru Yoshida, Tomoichiro Asano, Masayuki Komada, Naoyuki Kataoka, Kazuhiro Chida, Fumihiko Hakuno and Shin-Ichiro Takahashi _

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Oncotarget. 2018; 9:33871-33883. https://doi.org/10.18632/oncotarget.26049

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Haruka Furuta1, Hidehito Yoshihara1, Toshiaki Fukushima2,3, Yosuke Yoneyama1,6, Akihiro Ito4, Claire Worrall5, Ada Girnita5, Leonard Girnita5, Minoru Yoshida4, Tomoichiro Asano2, Masayuki Komada3, Naoyuki Kataoka1, Kazuhiro Chida1, Fumihiko Hakuno1 and Shin-Ichiro Takahashi1

1Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan

2Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan

3Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan

4Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama, Japan

5Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden

6Present address: Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence to:

Shin-Ichiro Takahashi, email: [email protected]

Fumihiko Hakuno, email: [email protected]

Keywords: ubiquitin; USP9X; IGF-I; IRS-2; prostate cancer

Received: March 07, 2018    Accepted: July 21, 2018    Published: September 21, 2018


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.

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