PROCA11 early activation fuels prostate cancer neuroendocrine traits by regulating cell survival and migration

Tumor plasticity drives the emergence of castration-resistant and neuroendocrine prostate cancer following androgen-deprivation therapy (ADT). Non-genetic determinants, including long non-coding (lnc)RNAs, preceding the acquisition of neuroendocrine traits, can disrupt androgen dependence and promote resistance. However, the precise transcriptome dynamics prior to therapy-induced neuroendocrine <i>trans</i>-differentiation remains unknown. Using a prostate cancer model mimicking the onset of castration-resistant and neuroendocrine phenotypes, we uncovered rapid lncRNA changes, with PROCA11 emerging as the most prominent. PROCA11 is highly expressed in advanced adenocarcinoma and neuroendocrine prostate cancer tumors. This predominantly nuclear lncRNA is rapidly activated upon hormone depletion and persists in neuroendocrine-like cells. PROCA11 promotes cell survival, proliferation, and motility by reducing apoptosis and enhancing adhesion, contributing to neuroendocrine traits. PROCA11 binds to the cell-cycle regulator CCAR2/DBC1 and to CTNNA1, controlling cell adhesion and cytoskeleton. We suggest that PROCA11 arises early during tumor plasticity and controls the development of castration-resistant and neuroendocrine phenotypes in prostate cancer.