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Prostate cancer

Twist and Skp2 castration resistance

Nature Reviews Urology volume 14, page 387 (2017)Cite this article

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The Twist transcription factor is overexpressed in castration-resistant tumour cells and is known to be a key driver towards EMT and CSC acquisition. Furthermore, Twist overexpression leads to resistance to paclitaxel and Twist inactivation inhibits prostate cancer growth and migration. Despite the fact that 90% of malignant prostate cancers exhibit upregulation of Twist, the mechanisms by which this arises is unclear. The F-Box protein Skp2 is a component of the SCF E3 ubiquitin ligase complex that is overexpressed in prostate cancer, and correlates with tumour stage, disease recurrence, and worse patient survival. Evidence from xenograft studies suggests that Skp2 also has a role in castration resistance.

In order to investigate the roles of Skp2 in prostate cancer, Ruan and co-workers began by crossing Skp2-null mice with TRAMP mice (which spontaneously develop prostate cancer) and compared tumorigenesis in wild-type, TRAMP, and TRAMP/Skp2−/− models. At analysis, 100% of TRAMP mice had developed tumours, compared with just one of 15 age-matched TRAMP/Skp2−/− mice, suggesting a role for Skp2 in tumorigenesis. Further follow-up monitoring revealed that Skp2 knockout inhibited metastasis and markedly improved overall survival, suggesting that targeting Skp2 could be a potential approach to prevent or treat CRPC.

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References

  1. Ruan, D. et al. Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist. Oncogene http://dx.doi.org/10.1038/onc.2017.64 (2017)

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  1. Annette Fenner
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Fenner, A. Twist and Skp2 castration resistance. Nat Rev Urol 14, 387 (2017). https://doi.org/10.1038/nrurol.2017.56

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