Transcriptional rewiring in cancer driven by POLR2A/RPB1: mechanistic insights, non-coding RNA crosstalk, and therapeutic opportunities

RNA polymerase II, together with its catalytic subunit RPB1 (encoded by <i>POLR2A</i>), forms the core of the eukaryotic transcriptional machinery that drives the synthesis of protein-coding and regulatory RNA transcripts. Accumulating evidence indicates that dysregulation of <i>POLR2A</i>/RPB1 is a critical driver of oncogenesis, promoting uncontrolled proliferation, evasion of apoptosis, and extensive transcriptional reprogramming across multiple malignancies, frequently affected by recurrent 17p deletions co-occurring with major tumor suppressor loss events. Such coordinated genomic alterations create transcriptional dependency that may be exploited therapeutically. Beyond its canonical role in transcription, <i>POLR2A</i>/RPB1 operates within an extensive regulatory network involving non-coding RNAs. Notably, circular RNAs derived from the <i>POLR2A</i> transcript have emerged as stable post-transcriptional regulators that modulate tumorigenic signaling pathways. In these roles, circular <i>POLR2A</i> isoforms promote proliferation, migration, and therapy resistance in glioblastoma and clear-cell renal cell carcinoma by acting as miRNA sponges or by scaffolding protein complexes that activate pathways such as ERK. These findings suggest that disturbances in <i>POLR2A</i> function reshape not only transcriptional output but also the broader non-coding RNA landscape, thereby reinforcing malignant phenotypes. Moreover, pharmacological agents such as triptolide further highlight transcription-dependent vulnerabilities by destabilizing RPB1, offering promising therapeutic opportunities, particularly in drug-resistant cancers. Collectively, <i>POLR2A</i>/RPB1 emerges as a central node linking transcriptional control, noncoding RNA biogenesis, and oncogenic signaling, positioning it as a compelling candidate for biomarker development and targeted therapeutic intervention.