Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import

Abstract

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.

Dysregulated Alternative Splicing Landscape Identifies Intron Retention as a Hallmark and Spliceosome as a Therapeutic Vulnerability in Aggressive Prostate Cancer

“…S2B) whereas GO terms ‘DNA damage’, ‘immunity’, and ‘nuclear pore’ were enriched in CRPC (Supplementary Fig. S2C), consistent with recent reports (30). Interestingly, and as expected, GO terms ‘SCs and development’ and ‘neuron and cell projection’ were greatly enriched in CRPC-NE (Supplementary Fig.…”

Depletion of nuclear pore protein NUP210 suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response

“…To test our hypothesis, we performed a cytokine array using the cultured supernatant of sh-Ctrl and Nup210 knockdown cells. Consisent with the transcriptome data, decreased secretion of cytokines (IL-1α), chemokines (CCL2, CXCL1), and adhesion molecules 21 (POSTN, SERPINE1) was observed in Nup210 knockdown 4T1 cells ( Fig. 8a, 8b).…”

“…Since many of our polymorphic metastasis susceptibility genes were identified as chromatin-associated factors, we hypothesized that germline polymorphism can affect metastasis through alteration of the cancer cell's epigenome.To identify metastasis-associated polymorphisms in the non-coding regulatory regions of the genome, we performed genome-wide identification of polymorphic accessible chromatin regions in mouse models of metastasis and identified Nup210, a gene encoding a nuclear pore complex protein, as a potential metastasis susceptibility gene. Although nuclear pore complex proteins have recently been shown to be associated with several developmental disorders and cancers [18][19][20][21] , their function in metastasis remains unexplored. Here, we established a nucleocytoplasmic transportindependent role of NUP210 in promoting lung metastasis in mouse models of breast cancer through alteration of mechanosensation, focal adhesion, and cell migration.…”

Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth

“…Oncogenic Myc drives aggressive and metastatic prostate cancer (16). Therefore, we began this study by conducting a global metabolomics screening (ϳ5,000 metabolites, first metabolomic screen) in prostate adenocarcinoma PC3 cells transfected with nontargeted siRNA or Myc-directed siRNA.…”