SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

Wenjian Gan, Xiangpeng Dai, Andrea Lunardi, Zhen Li, Hiroyuki Inuzuka, Pengda Liu, Shoreh Varmeh, Jinfang Zhang, Liang Cheng, Yin Sun, John M. Asara, Andrew H. Beck, Jiaoti Huang, Pier Paolo Pandolfi, Wenyi Wei

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81 Scopus citations

Abstract

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (δERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/δERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer. Gan et al. report that the Cullin 3<sup>SPOP</sup> E3 ubiquitin ligase plays a critical tumor-suppressive role in prostate cancer by negatively controlling ERG stability. Therefore, either SPOP mutation or ERG fusion can lead to elevated ERG protein levels by evading the SPOP-mediated degradation pathway to promote prostate cancer progression.

Original languageEnglish (US)
Pages (from-to)917-930
Number of pages14
JournalMolecular Cell
Volume59
Issue number6
DOIs
StatePublished - Sep 17 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Gan, W., Dai, X., Lunardi, A., Li, Z., Inuzuka, H., Liu, P., Varmeh, S., Zhang, J., Cheng, L., Sun, Y., Asara, J. M., Beck, A. H., Huang, J., Pandolfi, P. P., & Wei, W. (2015). SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression. Molecular Cell, 59(6), 917-930. https://doi.org/10.1016/j.molcel.2015.07.026