Multifaceted role of primary cilia and ciliary proteins: A potential nexus for hedgehog signaling and prostate cancer.

The primary cilium is a solitary, non-motile, microtubule-based organelle that extends from the cell membrane and functions as a critical coordinator of multiple signaling pathways. Despite its association with hundreds of proteins, only a subset is essential for its biogenesis and signal transmission. Malfunctions in primary cilia are associated with developmental disorders and various malignancies, including prostate cancer (PCa). Recent studies highlight the regulation of ciliogenesis, cilia length, and interaction among cilia-resident proteins, particularly within the ciliary hedgehog (Hh) signaling axis in oncogenesis, thereby positioning primary cilia as potential therapeutic targets. Nevertheless, the precise contribution of ciliary components to Hh pathway modulation in PCa remains poorly defined. This review integrates emerging evidence to elucidate the current state of knowledge on the structural and functional attributes of primary cilia, cilia-mediated molecular dynamics with Hh signaling, and their intersection in the context of PCa progression, including prostate development, carcinogenesis, and tumor microenvironment dynamics. Particular emphasis is placed on cilia-associated proteins, such as SCL/TAL1 interrupting locus (STIL), intraflagellar transport (IFT) family proteins, ADP-ribosylation factor (Arf) family proteins, transforming acidic coiled-coil protein-3 (TACC3), mitotic kinase Aurora A, and dual-specificity tyrosine-regulated kinase (DYRK), which have been mechanistically linked to PCa and modulate Hh signaling. However, their detailed contributions remain insufficiently characterized and warrant further investigation. This review underscores the role of primary cilia in PCa progression, highlights unresolved mechanistic gaps in their regulation, and proposes future directions for targeted molecular and therapeutic research.