A new study has uncovered an unexpected molecular player that helps make cancer cells stress-resilient. 

Researchers have identified the enzyme DHX8 as a crucial regulator of the stress‑response protein HSF1, which may have potential to open new avenues for future drug development. 

The findings, published in the journal NAR Cancer, reveal that DHX8 controls a critical processing step in the production of the HSF1 protein. HSF1’s normal function is to control the activity of hundreds of genes that enable healthy cells to cope with cellular stresses – especially helping them deal with misfolded proteins. 

This management of protein quality control in response to cell stress and ageing is beneficial to healthy cells. However, HSF1 can be hijacked by cancers to protect them from the challenging collateral damage caused by activation of cancer-causing oncogenes. By disrupting DHX8 in multiple cancer cell types, the research team demonstrated a striking collapse in this protective network, leading to impaired cell growth and, in some cases, cancer‑selective cell death. 

The researchers at The Institute of Cancer Research, London also discovered that specific genetic knockdown or targeted degradation of the DHX8 protein has additional effects on wider processes that contribute to cancer. Particularly affected was a well‑established HSF1‑regulated cancer gene signature known to be associated with poor clinical outcomes in cancer patients. 

Co-senior author Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics and Group Leader in Signal Transduction and Molecular Pharmacology at the ICR, said: “This study stands as a compelling example of how unbiased functional genomic screening, followed by digging into the intricacies of RNA biology, can surface unexpected vulnerabilities in cancer.  The next step will be to develop small-molecule tools that can help dissect DHX8’s functions more precisely and act as pathfinder molecules for potential therapeutics.”