A novel lncRNA PROCA11 regulates cell plasticity in response to androgen deprivation of prostate cancer cells

Long non-coding RNAs (lncRNAs) represent vast and yet poorly characterized family of genes that can fine tune cellular plasticity, thereby allowing the emergence of aggressive therapy-resistant and metastatic cancers. Androgen deprivation therapies (ADT) are commonly used to treat prostate cancer by inactivating the Androgen Receptor (AR). However, castration-resistant prostate cancer (CRPC) with neuroendocrine subtypes (NEPC) often emerge. In this study, we explore the role of lncRNAs in response to androgen deprivation. Using a dynamic prostate cancer cell system mimicking the CRPC and NEPC onset, we identified 15 novel lncRNAs, with PROCA11 standing out as a first-choice candidate, being also highly abundant in high-risk prostate cancer tumors. This majorly nuclear lncRNA is expressed at low levels in androgen-dependent conditions of growth and strongly activated upon hormone withdrawal, preceding neuroendocrine genes and persisting at high levels in neuroendocrine cells. Extensive computational analysis of clinical data and functional studies in cells revealed PROCA11 association with basal-to-luminal transformation of the transcriptomic landscape and activation of metabolic and signaling pathways reminiscent of neurogenesis and of maintenance of AR signaling. We propose that PROCA11 is involved in the intricate circuits regulating cellular plasticity enabling cell survival and proliferation and emergence of the NE phenotype in response to ADT.