Figure 4 |Lineage plasticity and phenotype switching. After long-term AR inhibition by Enz, the phenotypes and cell lineage alter, leading to the EMT or neuroendocrine differentiation. The EMT drivers and mesenchymal markers are shown in the lower left corner of cell. TGF-β plays a critical role in EMT process and involve diverse signalling pathways. Inhibiting TGF-β-related targets can overcome Enz resistance. The loss of RB1 and TP53 facilitates lineage plasticity and epigenetic reprogramming factors such as EZH2, SOX2, and SOX9 have effects in neuroendocrine differentiation. In particular, the loss of CHD1 contributes to anti-androgen resistance and four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) are found to participate in Enz resistance. EMT, epithelial-mesenchymal transition; TGF-β, transforming growth factor β; CCND1, cyclin D1; SMAD3, SMAD family member 3; LY2157299, TGF-β receptor I kinase inhibitor; Metformin, a TGF-β1/STAT3 axis inhibitor; IGFBP-3, insulin-growth factor binding protein-3; DZ-50, IGFBP-3 inhibitor; RB1, retinoblastoma tumour suppressor gene; TP53, transformation-related protein 53; TSP1, thrombospondin-1; REST, RE1-silencing transcription factor; SRRM4, serine/arginine repetitive matrix 4; SPINK1, serine peptidase inhibitor, Kazal type 1; BRD4, bromodomain-containing protein 4; HOXB13, a lineage-specific homeodomain-containing transcription factor; BRN2, a neural transcription factor; MUC1, Mucin 1; (PKC)λ/ι, protein kinase C; ATF4, activating transcription factor 4; PHGDH, phosphoglycerate dehydrogenase; SAM, S-adenosyl methionine; CHD1, a prostate cancer gene leads to anti-androgen resistance.