# Human DEAH-box helicase 8 regulates HSF1-mediated stress response and cancer-associated pre-mRNA splicing in tumour cells

## TL;DR

This study shows that DHX8, an RNA helicase, regulates HSF1 and cancer-related gene splicing, making it a potential target for cancer therapy.

## Contribution

DHX8 is identified as a novel regulator of HSF1 and cancer-associated pre-mRNA splicing, with potential therapeutic implications.

## Key findings

- DHX8 silencing reduces HSF1 protein by causing intron retention in its transcripts.
- Loss of DHX8 alters RNA processing of cancer-associated genes linked to poor outcomes.
- DHX8 silencing induces apoptosis more effectively in cancer than in non-tumorigenic cells.

## Abstract

Transcription factor heat shock factor 1 (HSF1) orchestrates the cellular stress response, promoting malignant transformation, unchecked proliferation, and stress-resilient survival of tumour cells. We set out to discover potentially druggable regulators of HSF1 activation and identified DEAH-box RNA helicase 8 (DHX8). We investigated the role of DHX8 in regulating HSF1 within the broader context of DHX8 function in cancer cells. DHX8 silencing induces intron retention in HSF1 transcripts, reducing HSF1 protein. Importantly, DHX8 loss significantly alters RNA processing of an HSF1-regulated cancer-associated gene signature linked to poor clinical outcomes, as well as additional oncogenic and stress-response pathways. DHX8 binds between the pre-messenger RNA (mRNA) lariat branch point and the 3′ splice site, consistent with the predominance of intron-retained transcripts following DHX8 loss. We show that both the ATPase and RNA-binding activities of DHX8 are essential for its role in splicing, including processing of HSF1 mRNA. We also find that DHX8 silencing triggers apoptosis more effectively in human cancer cells than in non-tumorigenic cells. Our findings identify DHX8 as a critical regulator of stress-adaptive gene expression, highlighting its promise as a therapeutic target not only to disrupt HSF1-dependent transcriptional programs but also having broader effects in cancer cells under oncogenic stress.

Graphical Abstract