The driver role of JAK-STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy- and castration-resistant prostate cancer

Background Lineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy- and castration-resistant PCa (t-CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy. Methods Various PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti-tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t-CRPC model. Results We demonstrated the role of interferon-related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK-STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK-STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR-128 and -101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t-CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability. Conclusions This study provides a critical role of STAT1-IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t-CRPC.

Automated summary

This study identifies the role of interferon-related signaling pathway and IFIT5 in promoting prostate cancer stemness and highlights the potential of JAK or STAT1 inhibitors in preventing therapy-resistant prostate cancer. Inhibition of JAK-STAT1 signaling suppresses the capabilities of cancer stem cells and knocking down IFIT5 reduces cancer stemness and tumor initiating capability.