Abstract
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2–nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial–mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.
Highlights
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood
We propose that the CITED2–NCL signaling pathway is a potential target for treating prostate cancer metastasis
We examined CITED2 expression in 28 different types of cancer using The Cancer Genome Atlas (TCGA) database and found relatively high CITED2 messenger RNAs (mRNAs) levels in thyroid, kidney, ovarian, lung, prostate, breast, and lung cancers (Fig. 1a)
Summary
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 acts as a coactivator of activator protein 2 (AP2) transcription factors by recruiting p300/CBP to AP-2 target genes[6]. CITED2 is suspected to be extensively involved in prostate cancer, since its expression is induced by an ETS family member ELK119, which has been reported to recruit AR to activate growth signaling in prostate cancer cells[20]. NCL is an RNA-binding nulceolar protein which has been reported to stimulate cancer progression and metastasis[21,22,23], the exact underlying mechanism has not been determined. We found that CITED2 was highly expressed in metastatic prostate cancer because of TMPRSS2– ERG gene fusion, which promoted metastasis by activating NCL at the post-translational level. We propose that the CITED2–NCL signaling pathway is a potential target for treating prostate cancer metastasis
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