Inhibition of KPNA4 attenuates prostate cancer metastasis

Abstract

Prostate cancer (PCa) is a common cancer in men. Although current treatments effectively palliate symptoms and prolong life, the metastatic PCa remains incurable. It is important to find biomarkers and targets to improve metastatic PCa diagnosis and treatment. Here, we report a novel correlation between karyopherin α4 (KPNA4) and PCa pathological stages. KPNA4 mediates the cytoplasm-to-nucleus translocation of transcription factors including NF-κB while its role in PCa was largely unknown. We find that knockdown of KPNA4 reduces cell migration in multiple PCa cell lines, suggesting a role of KPNA4 in PCa progression. Indeed, stable knockdown of KPNA4 significantly reduces PCa invasion and distant metastasis in mouse models. Functionally, KPNA4 alters tumor microenvironment in terms of macrophage polarization and osteoclastogenesis by modulating TNF-α and -β. Further, KPNA4 is proved as a direct target of miR-708, a tumor-suppressive miRNA. We disclose the role of miR-708-KPNA4-TNF axes in PCa metastasis and KPNA4’s potential as a novel biomarker for PCa metastasis.

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

“…The loss of function assay revealed that KPNA4-mediated nuclear transport is required for HNSCC proliferation. Recent studies demonstrated that certain karyopherins are elevated in several cancers and can regulate malignant phenotypes by affecting cytoplasmnuclear transport systems [25,[30][31][32][33][34]. Taken together, these results indicate that targeting disease-specifically altered transport systems may serve as promising therapeutic strategies for cancer treatment.…”

A meta-analysis of genome-wide association studies of epigenetic age acceleration

“…Three genes at 6p22.3, NHLRC1 , TPMT , and KDM1B , had the lowest P -values of 1.251×10 −23 , 4.639×10 −23 , and 7.68×10 −11 respectively; all these genes are involved in metabolism-related pathways (27,29,30). Although containing no genome-wide significant SNPs, 3q25.33 appears to be an important genomic region for Horvath-EAA, with four significantly associated genes including TRIM59 and KPNA4 , which play roles in the immune system (31,32). Two further significant genes are FAIM and TERT , whose functions include apoptosis and autophagy (24), and telomere length-associated ageing and apoptosis (33,34) respectively.…”

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

“…Apart from TRIM59, the eQTL colocalization also implicated other genes associated with cancer progression (e.g. KPNA4, SMC4, and CXXC4) [58,59,60]. SMC4 is known to inhibit cellular senescence in replicating cells [61,62].…”