# RBM10 modulation of circRNA biogenesis contributes to its tumor suppressor role in lung adenocarcinoma

## TL;DR

This study shows how the protein RBM10 helps control the production of circular RNAs, which act as tumor suppressors in lung adenocarcinoma.

## Contribution

The paper reveals a new mechanism by which RBM10 regulates circRNA biogenesis, linking it to tumor suppression in lung cancer.

## Key findings

- RBM10 binds to intronic regions of circHIPK3 and circSMARCA5, promoting their circularization through position-dependent exon skipping.
- Loss of RBM10 leads to reduced levels of circHIPK3 and circSMARCA5, which correlates with increased tumorigenicity in lung adenocarcinoma.
- circHIPK3 is downregulated in RBM10-mutant tumors and may serve as a biomarker and therapeutic target in LUAD.

## Abstract

Circular RNAs (circRNAs) are emerging regulators in cancer biology, yet the mechanisms underlying their biogenesis remain incompletely defined. RBM10, a splicing regulator frequently mutated in lung adenocarcinoma (LUAD), modulates RNA processing, but its involvement in circRNA regulation has not yet been addressed. Transcriptomic profiling of RBM10-restored LUAD cells, followed by RT-qPCR validation, identified circHIPK3 and circSMARCA5 as consistently RBM10-dependent circRNAs. Subcellular fractionation confirmed nuclear confinement of RBM10 and cytoplasmic enrichment of circRNAs, supporting a nuclear role for RBM10 in circRNA biogenesis. PAR-CLIP and RNA pulldown assays demonstrated direct RBM10 binding to intronic flanking regions of these circRNAs. Using a splicing reporter assay, we found that RBM10 binding to the 3' flanking region promotes exon skipping and circularization more efficiently than 5' binding, revealing a position-dependent mechanism controlling circRNA output. Analysis of RBM10 point mutants showed impaired regulation of circHIPK3 and circSMARCA5, linking defective exon skipping to disrupted circRNA formation. Functionally, modulation of circHIPK3 and circSMARCA5 phenocopied RBM10 restoration in mutant LUAD cell lines and rescued the tumorigenic phenotype driven by RBM10 loss. In two independent LUAD cohorts, circHIPK3 was consistently downregulated, particularly in RBM10-mutant tumors, and strongly correlated with RBM10 expression. Proteomic analyses further identified RBM10–SF3B1 interaction as a key upstream event governing circHIPK3 biogenesis. Together, these findings uncover a previously unrecognized mechanism through which RBM10 exerts tumor-suppressive functions via circRNA regulation and highlight circHIPK3 as a promising biomarker and potential therapeutic target in RBM10-deficient LUAD.

The online version contains supplementary material available at 10.1186/s40364-026-00891-6.