The Circadian–Spliceosome Axis: A Temporal Dimension of Transcriptomic Heterogeneity in Prostate Cancer

Abstract

Molecular heterogeneity and therapeutic resistance drive treatment failure in advanced prostate cancer. While alternative splicing and transcript isoform remodeling—epitomized by the resistance-associated androgen receptor variant AR-V7—are critical to this plasticity, the upstream dynamic mechanisms controlling transcript-level diversification remain poorly understood. In this perspective, we propose a novel conceptual framework: the circadian–spliceosome axis. We hypothesize that core circadian networks (including BMAL1, CLOCK, PER, and CRY) act as higher-order temporal organizers that actively modulate RNA-processing machinery, enabling tumor cells to dynamically explore non-genetic, adaptive transcriptomic states under therapeutic pressure. Validating this temporal dimension requires integrating long-read sequencing, single-cell transcriptomics, and longitudinal sampling. Formalizing the circadian–spliceosome axis will expand current models of non-genetic tumor adaptation and open new avenues for chronobiology-informed precision oncology to disrupt resistance phenotypes before they become immutable.