A new study has identified a novel mechanistic role for nucleoporin POM121 in prostate cancer progression.

Initial transcriptomic profiling of nuclear pore complex composition in clinical tumour samples identified a subset of nucleoporins that are deregulated during primary-to-metastatic disease progression. A subsequent genetic loss-of-function screen implicated POM121 — the top upregulated nucleoporin — as a key mediator of aggressive tumour biology in vitro and in vivo.

Immunoprecipitation and knockdown assays showed that POM121 exerts its oncogenic effects by enhancing nuclear import through direct interaction with importin-β, a nuclear import machinery component. Transcriptomic profiling of aggressive prostate cancer cell lines and clinical specimens revealed a common POM121-associated target gene signature related to those of transcription factors MYC and E2F1. Further mechanistic characterization showed that POM121 controls importin-β-dependent nuclear shuttling and signalling of the transcription factors MYC, E2F1, and GATA2, and the androgen receptor (AR).

Treatment of aggressive prostate cancer cells with the importin-β inhibitor importazole decreased tumorigenicity, proliferation, therapeutic resistance, and MYC, E2F1, GATA2, and AR nuclear localization. Consistently, importazole (alone or with chemotherapy) improved overall survival and reduced tumour burden and Ki67 expression in xenograft mouse models.

Overall, POM121 enhances prostate cancer aggressiveness by regulating the nuclear localization and activity of key transcription factors, a mechanism that could be therapeutically targeted by disrupting the nuclear import machinery. “In future studies, we will try to identify the tumours that might benefit the most from this strategy, such as those driven by specific transcription factors,” concludes author Josep Domingo-Domenech.