Inhibition of Karyopherin beta 1 suppresses prostate cancer growth

Jian Yang, Yuqi Guo, Cuijie Lu, Ruohan Zhang, Yaoyu Wang, Liang Luo, Yanli Zhang, Catherine H. Chu, Katherine J. Wang, Sabrine Obbad, Wenbo Yan, Xin Li

Research output: Contribution to journalArticle

Abstract

Prostate cancer (PCa) initiation and progression requires activation of numerous oncogenic signaling pathways. Nuclear-cytoplasmic transport of oncogenic factors is mediated by Karyopherin proteins during cell transformation. However, the role of nuclear transporter proteins in PCa progression has not been well defined. Here, we report that the KPNB1, a key member of Karyopherin beta subunits, is highly expressed in advanced prostate cancers. Further study showed that targeting KPNB1 suppressed the proliferation of prostate cancer cells. The knockdown of KPNB1 reduced nuclear translocation of c-Myc, the expression of downstream cell cycle modulators, and phosphorylation of regulator of chromatin condensation 1 (RCC1), a key protein for spindle assembly during mitosis. Meanwhile, CHIP assay demonstrated the binding of c-Myc to KPNB1 promoter region, which indicated a positive feedback regulation of KPNB1 expression mediated by the c-Myc. In addition, NF-κB subunit p50 translocation to nuclei was blocked by KPNB1 inhibition, which led to an increase in apoptosis and a decrease in tumor sphere formation of PCa cells. Furthermore, subcutaneous xenograft tumor models with a stable knockdown of KPNB1 in C42B PCa cells validated that the inhibition of KPNB1 could suppress the growth of prostate tumor in vivo. Moreover, the intravenously administration of importazole, a specific inhibitor for KPNB1, effectively reduced PCa tumor size and weight in mice inoculated with PC3 PCa cells. In summary, our data established the functional link between KPNB1 and PCa prone c-Myc, NF-kB, and cell cycle modulators. More importantly, inhibition of KPNB1 could be a new therapeutic target for PCa treatment.

Original languageEnglish (US)
JournalOncogene
DOIs
StatePublished - Jan 1 2019

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beta Karyopherins
Prostatic Neoplasms
Growth
Cell Cycle
Karyopherins
Neoplasms
Cell Nucleus Active Transport
NF-kappa B
Nuclear Proteins
Tumor Burden
Mitosis
Heterografts
Genetic Promoter Regions
Chromatin
Prostate
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Inhibition of Karyopherin beta 1 suppresses prostate cancer growth. / Yang, Jian; Guo, Yuqi; Lu, Cuijie; Zhang, Ruohan; Wang, Yaoyu; Luo, Liang; Zhang, Yanli; Chu, Catherine H.; Wang, Katherine J.; Obbad, Sabrine; Yan, Wenbo; Li, Xin.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Yang, J, Guo, Y, Lu, C, Zhang, R, Wang, Y, Luo, L, Zhang, Y, Chu, CH, Wang, KJ, Obbad, S, Yan, W & Li, X 2019, 'Inhibition of Karyopherin beta 1 suppresses prostate cancer growth', Oncogene. https://doi.org/10.1038/s41388-019-0745-2
Yang, Jian ; Guo, Yuqi ; Lu, Cuijie ; Zhang, Ruohan ; Wang, Yaoyu ; Luo, Liang ; Zhang, Yanli ; Chu, Catherine H. ; Wang, Katherine J. ; Obbad, Sabrine ; Yan, Wenbo ; Li, Xin. / Inhibition of Karyopherin beta 1 suppresses prostate cancer growth. In: Oncogene. 2019.
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