Abstract
POM121 is upregulated in aggressive and lethal prostate cancers and promotes tumor growth in vivo.
Major finding: POM121 is upregulated in aggressive and lethal prostate cancers and promotes tumor growth in vivo.
Mechanism: POM121 interacts with importin β to promote the nuclear import of MYC, E2F1, AR, and GATA2.
Impact: The POM121–importin β axis may represent a therapeutic target to reduce prostate tumor aggressiveness.
Nuclear pore complexes are large transmembrane cylinders composed of nucleoporins that perforate the nuclear envelope to regulate nuclear–cytoplasmic transport, transcription, and genome integrity. Several nucleoporins have been linked to tumorigenesis, but their roles in cancer are not well understood. Rodriguez-Bravo and colleagues sought to investigate the role of nucleoporins in prostate cancer aggressiveness. Analysis of nucleoporin gene expression profiles in primary prostate tumor samples and lethal advanced prostate tumors, along with transmission electron microscopy, revealed a distinct nucleoporin composition associated with aggressive and lethal prostate cancer. A loss-of-function genetic screen uncovered the nucleoporin POM121 as a key regulator of prostate cancer aggressiveness. POM121 was upregulated in advanced lethal prostate tumors, and its depletion disrupted nuclear import and suppressed prostate cancer cell growth in soft agar without altering nuclear pore complex integrity. In vivo, depletion of POM121 suppressed tumor growth and aggressiveness and enhanced the efficacy of chemotherapy in prostate cancer xenografts. RNA-sequencing revealed that POM121 depletion was associated with downregulation of target genes of the oncogenic transcription factors MYC and E2F1. Mechanistically, POM121 interacted with importin β at the nuclear pore to enhance the importin-dependent import of MYC and E2F1 and the prostate-cancer specific transcription factors AR and GATA2 into the nucleus, thereby promoting expression of genes that drive aggressive prostate cancer. Further, GATA2 enhanced transcription of POM121, which in turn promoted the nuclear import of GATA2 to enhance its activity, creating a positive regulatory feedback loop that promotes tumor aggressiveness. These findings suggest the potential for targeting the POM121–importin β axis, and, indeed, the importin β inhibitor importazole suppressed the growth of patient-derived prostate cancer xenografts. Collectively, these findings demonstrate a role for POM121 in regulating prostate cancer aggressiveness and indicate that the POM121–importin β axis may represent a therapeutic target in these tumors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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