Loss of ESE3/EHF is sufficient to promote cell plasticity, transformation and androgen-independent status in the early stage of prostate carcinogenesis.

Phenotypic plasticity enables tumor progression and treatment resistance. However, its timing and underlying mechanisms are poorly understood. Here, we demonstrate that cell plasticity can emerge early during prostate cancer development, resulting from the knockout of the epithelial-specific ETS transcription factor EHF in prostate epithelial cells. Inspecting the transcriptome of human prostate cancers, we identified a correlation between low EHF expression, loss of luminal epithelial identity, and attenuated androgen signaling in both primary tumors and castration-resistant prostate cancers (CRPC). In EHF knockout mouse models and human epithelial cells, EHF ablation was sufficient to disrupt epithelial cell lineage integrity and promote a progenitor/stem cell-like state with both basal and luminal features, enabling high plasticity and multi-lineage phenotypic transitions. Mechanistically, EHF acted as a central node controlling a hierarchy of transcriptional regulatory factors and downstream signaling pathways (e.g., COL1A1/DDR1, JAK/STAT3), thereby regulating epithelial lineage integrity and restricting stemness and phenotypic transitions. Activation of these downstream pathways, consequent to EHF loss, promoted non-luminal cell features, attenuated androgenic response, and resistance to AR antagonists. Collectively, these data provide novel insights into the causes of phenotypic plasticity and androgen indifference already at the early stages of prostate tumorigenesis and a new perspective on the paths to cancer progression directly relevant to the development of more efficient treatment strategies.