Transcriptome profiles of POM121-knockout prostate cancer cell lines

Nucleoporins are major constituents of nuclear pore complexes, molecular conglomerates embedded within the nuclear envelope that participate in bidirectional trafficking between nucleus and cytoplasm, chromatin silencing and organization, and transcriptional regulation . This functional vantage point is of utmost importance for fundamental cell processes such as intracellular signaling, cell migration, DNA repair and cell division, all of which can be impaired when the molecular identity of the NE and nuclear pore complex is compromised, as seen in cancer. Here we identify a nucleoporin POM121 as a key regulator of proliferation, tumourigenesis, and survival in chemoresistant prostate cancer. Mechanistically, POM121 regulates nuclear transport of specific survival-conferring transcription factors (MYC and E2F1) and androgen receptor that have been previously linked with advanced stages of prostate cancer. POM121-mediated deregulation of nucleocytoplasmic transport occurs through its interaction with Importin β, which serves as a pharmacological target that decreases tumour growth, sensitizes the tumor cells to standard chemotherapy, and improves survival of patient-derived xenograft mice. These results indicate that nuclear pore complex represents a novel mechanism of chemoresistance, which can be therapeutically targetable in aggressive prostate cancer.