The pseudogene derived transcript SUZ12P activates SUZ12 transcription through an RB1-E2F1 regulatory axis in lung cancer

Abstract

Genome-wide studies have identified thousands of pseudogenes in the human genome, many of which are now recognized as functional regulators rather than inert genomic relics. Increasing evidence indicates that pseudogene-derived transcripts play critical roles in cancer; however, the role and mechanism of pseudogene-derived transcripts in non–small cell lung cancer (NSCLC) remain largely unclear. We analyzed NSCLC transcriptome datasets to screen dysregulated pseudogenes. We verified SUZ12P expression in clinical samples and evaluated its prognostic value. Gain- and loss-of-function assays were performed to assess SUZ12P effects on NSCLC cell proliferation, migration, invasion, xenograft growth and lung metastasis in vitro and in vivo. RNA pull-down, mass spectrometry, RIP, co-IP and ChIP were used to explore molecular interactions. Palbociclib was applied to test therapeutic potential of the SUZ12P/RB1 axis. SUZ12P was significantly upregulated in NSCLC and correlated with distant metastasis and poor overall survival. SUZ12P promoted NSCLC tumor growth and metastasis in vitro and in vivo. Mechanistically, SUZ12P directly bound the RBC domain of RB1, blocked PP1c–RB1 interaction, enhanced RB1 phosphorylation at Ser795/Ser807, and released E2F1. Activated E2F1 transcriptionally upregulated SUZ12 by binding its promoter, forming a SUZ12P/RB1/E2F1/SUZ12 regulatory axis. CDK4/6 inhibitor palbociclib disrupted this axis and reversed SUZ12P-driven oncogenic phenotypes. Pseudogene transcript SUZ12P is an oncogenic driver in NSCLC that acts through the RB1–E2F1 pathway to activate SUZ12 transcription. The SUZ12P/RB1/E2F1 axis is a novel prognostic biomarker and promising therapeutic target for NSCLC.