Molecular mechanisms driving lineage plasticity in prostate cancer: NANOG and beyond

Developing resistance to androgen receptor (AR) signaling inhibitors is a significant challenge in the treatment of castration-resistant prostate cancer. Prolonged use of inhibitors like enzalutamide can cause prostate cancer cells to undergo lineage reprogramming, transitioning to neuroendocrine subtypes that no longer rely on AR signaling. These neuroendocrine subtypes are among the most aggressive forms of prostate cancer. During this process of lineage plasticity, cancer cells experience extensive transcriptional rewiring and acquire stem-like properties characterized by increased stemness. Research has shown that prostate cancer cells gain these stem-like traits through the expression of stem cell-associated proteins such as NANOG, particularly under stable and accumulating conditions. The post-translational modification of NANOG at specific sites is critical for maintaining its stability, which in turn enhances the tumorigenic potential of the cells. This review discusses the mechanisms by which NANOG phosphorylation promotes stemness and lineage plasticity in prostate cancer.