Long Non-Coding RNAs Mediate Endocrine Signaling and Resistance in Prostate Cancer

Abstract

Prostate cancer (PCa) represents a hormone-dependent malignancy where androgen receptor (AR) signaling plays a central role in disease initiation, progression, and therapeutic resistance. Recent advances have revealed that long non-coding RNAs (lncRNAs) constitute a critical regulatory layer in prostate cancer, with implications for endocrine signaling pathways. lncRNAs orchestrate complex gene regulatory networks through diverse molecular mechanisms including chromatin remodeling, AR splice variant regulation, competitive endogenous RNA networks, translational control, and metabolic reprogramming. In castration-resistant prostate cancer, dysregulated lncRNAs contribute to resistance against androgen deprivation therapy and next-generation AR antagonists such as enzalutamide. This review synthesizes current knowledge on lncRNA biology in PCa, emphasizing lncRNA relationships with AR signaling and endocrine resistance mechanisms. We discuss key lncRNAs that modulate AR activity, metabolic adaptation, and lineage plasticity. Additionally, we examine structure-function relationships that enable rational therapeutic design, lncRNA roles in bone metastasis and neuroendocrine differentiation, and lncRNA clinical utility as biomarkers for disease progression and treatment stratification. Therapeutic strategies include antisense oligonucleotides, small-molecule inhibitors of lncRNA-protein interaction disruptors, and combination approaches with DNA-damaging agents and AR inhibitors. Understanding lncRNA-mediated endocrine regulation provides insights into prostate cancer biology and offers avenues for overcoming therapeutic resistance in advanced disease.