The SPOP-ITCH Signaling Axis Protects Against Prostate Cancer Metastasis

Jinlu Ma,Joshua S Fried,Bo Xu,Suxia Han,Xinyue Tan,Jie Chen,Mengjiao Cai,Yuan Ma,Yaqi Mo

doi:10.3389/fonc.2021.658230

Abstract

Prostate cancer is one of the most common causes of cancer incidence and death in men, with the mortality caused primarily by the late-stage and metastatic forms of the disease. The mechanisms and molecular markers for prostate cancer metastasis are not fully understood. Speckle type Poz Protein (SPOP) is an E3 ubiquitin ligase adaptor that is often mutated in prostate cancer. In this study, we sequenced the SPOP gene in 198 prostate cancer patients and found 16 mutations in the cohort. Multivariate analysis revealed that SPOP mutations correlated with the clinical stage of the disease and strongly with metastasis. We identified ITCH as a candidate protein for SPOP-mediated degradation via mass spectrometry. We demonstrated the interaction between SPOP and ITCH, and found that the SPOP F133L mutation disrupted the SPOP-ITCH interaction, leading to a subsequent increase in the ITCH protein level. Further, we found that the SPOP knockdown led to higher levels of Epithelial- mesenchymal transition (EMT) proteins and increased cell invasion. Together, our results highlight the functional significance of the SPOP-ITCH pathway in prostate cancer metastasis.

Highlights

Prostate cancer is among the leading causes of both cancer incidence and death in men [1]
We screened for somatic variants in Exons Six and Seven of the Speckle type Poz Protein (SPOP) gene in the prostate tumor tissues, as all the previously reported SPOP mutations were within these two exons
A multivariate analysis revealed the presence of SPOP mutations as an independent predictor of prostate cancer metastasis

Summary

Introduction

Prostate cancer is among the leading causes of both cancer incidence and death in men [1]. Previous genetic studies have found typical mutations/aberrations in prostate cancer, including ERG gene fusions, p53 aberrations, Androgen Receptor (AR) amplifications, and Speckle type Poz Protein (SPOP) missense mutations [3]. Recent studies on prostate cancer patients have revealed that the SPOP gene as the most common recurrent point mutations, with 8%–15% of the patient population carrying a somatic mutation in this gene [6,7,8,9,10,11]. Of these naturally occurring SPOP mutations, a significant proportion occurs in the substrate-binding

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Conclusion