# Cancer-associated fibroblast-induced lncRNA WARS2-IT1 confers radioresistance of colorectal cancer via enhancing HIF-1α stability

## TL;DR

This study shows how cancer-associated fibroblasts help colorectal cancer resist radiation by boosting a specific long noncoding RNA that stabilizes a key survival protein.

## Contribution

The study identifies WARS2-IT1 as a novel lncRNA mediating radioresistance in CRC via HIF-1α stabilization.

## Key findings

- CAFs from radioresistant CRC patients produce more TGF-β1, which induces WARS2-IT1 expression.
- WARS2-IT1 promotes radioresistance by stabilizing HIF-1α through interference with PHD2 interaction.
- Targeting WARS2-IT1 could be a promising strategy to overcome CRC radioresistance.

## Abstract

The tumor microenvironment in colorectal cancer (CRC) is marked by a diverse and abundant population of cancer-associated fibroblasts (CAFs), which play a crucial role in radioresistance. Nonetheless, the mechanisms through which CAFs contribute to radioresistance remain unclear. In this study, we demonstrate that CAFR, a specific subset of CAFs derived from radioresistant CRC patients, produces higher levels of transforming growth factor-β1 (TGF-β1) compared to CAFs isolated from radiosensitive CRC patients. Through long noncoding RNA (lncRNA) profiling of tumor cells treated with CAF-conditioned medium (CAF-CM), we identify WARS2-IT1 (WARS2 intronic transcript 1), whose expression is directly stimulated by TGF-β1 signaling. This lncRNA serves as a key player in promoting radioresistance and is essential for the TGFβ1-induced radioresistance pathway. Mechanistically, WARS2-IT1 interferes with the interaction between prolyl hydroxylase domain 2 (PHD2) and hypoxia-inducible factor-1α (HIF-1α), preventing the hydroxylation and subsequent degradation of HIF-1α. This process leads to the activation of glycolytic pathways, thereby enhancing radioresistance. Our findings underscore the potential of targeting CAF-driven WARS2-IT1 as a promising strategy to counteract tumor radioresistance in CRC.