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An important study has uncovered an unexpected molecular player that helps make cancer cells stress-resilient, thereby promoting the survival, growth and progression of tumours.
Researchers have identified the enzyme DHX8 as a crucial regulator of the stress‑response protein HSF1. This discovery deepens the scientific understanding of how cancers develop and resist treatment, and it 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 – a master regulator transcription factor. Known as the ‘guardian of the proteome’, 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 aging 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.
In follow-up work, 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.
Although the work, which was funded by Cancer Research UK, is still firmly in the realm of laboratory biology, this discovery offers a powerful insight into a fundamental stress-resilience mechanism exploited by tumours and lays the groundwork for future exploration of DHX8 as an indirect, and possibly more manageable, way to weaken HSF1 activity.
A hidden regulator emerges
HSF1 has long been recognised as a potent driver of malignancy. Cancer cells depend heavily on this protein to withstand the constant stress of activated cancer genes and the presence of mutated or misfolded proteins – conditions that would be debilitating or lethal without HSF1’s protection. However, HSF1 lacks obvious drug‑binding pockets, making it extremely challenging to target directly with drugs.
To overcome this barrier, the ICR team screened more than 7,500 ‘druggable genes’ to search for regulators of HSF1 that might represent alternative indirect targets. They looked for genes that decreased the activity of HSF1 in cancer cells by measuring expression of a gene whose activity depends on HSF1. Of all the hits emerging from the screen, DHX8 stood out as the strongest and most consistent.
DHX8 is known to function as part of a cellular machine called the spliceosome, acting as an RNA helicase that remodels RNA structures and known for its role in the late stages of messenger RNA (mRNA) splicing, prior to translation into protein.
The researchers showed that silencing DHX8 led to a large reduction in HSF1 protein levels, even though the amount of HSF1 mRNA remained largely unchanged. This pointed to a problem not with expression of the HSF1 gene itself but with processing of the corresponding HSF1 mRNA. Using a suite of advanced molecular techniques, the team demonstrated that DHX8 binds directly to HSF1 pre‑mRNA and is required for the removal of specific unwanted sequences known as ‘introns’ within the HSF1 mRNA.
Introns are non-coding sequences in genes and the corresponding mRNA molecules that must be removed from the pre-mRNA before the genetic information can be correctly translated from mRNA into protein. Without DHX8, these introns are retained, preventing mature HSF1 mRNA from forming and sharply reducing the amount of HSF1 protein available to activate stress‑response genes.
Notably, this effect appeared to be unique to DHX8. Knocking down other helicases that are also usually involved in splicing did not produce the same outcome, revealing a surprising specificity in how HSF1 is processed.
Broad consequences for cancer biology
Not surprisingly, the impact of DHX8 loss extended far beyond HSF1. When DHX8 was silenced or degraded in different cancer cell lines, the resulting cascade of faulty splicing affected thousands of transcripts, including those for many genes involved in stress adaptation, oncogenic signalling and cell‑cycle control. Particularly affected was a well‑established HSF1‑regulated cancer gene signature known to be associated with poor clinical outcomes in cancer patients.
Interestingly, cancer cells were shown to be dramatically more vulnerable than healthy cells to DHX8 disruption. In tumour cell lines, the absence of DHX8 triggered reduced proliferation, accumulation of cells at a critical checkpoint before division and, in some cases, clear signs of programmed cell death. Non‑tumorigenic cells, in contrast, showed much milder responses.
This difference is consistent with the idea that cancer cells operate under high levels of intrinsic stress and therefore rely more heavily on robust RNA processing and HSF1‑driven protective programmes, indicating a possible therapeutic selectivity.
While the new results identify and validate DHX8 as a cancer dependency and potential drug target, its role in the spliceosome means that any future therapy based on inhibiting DHX8 would need careful evaluation. Although cancer cells showed greater sensitivity in the laboratory, DHX8 is also essential to many normal cellular functions, and the long‑term cancer-selective therapeutic window remains uncertain. The potential toxicity of possible future DHX8 inhibitors would need to be investigated thoroughly before any potential clinical development.
A promising research direction
Nevertheless, the new findings identify a significant step in understanding the fundamental interplay between RNA processing, stress responses and cancer biology, providing a conceptual foundation for future research and possible therapies.
Co‑senior author Dr Paul Clarke, Group Leader in RNA Biology and Molecular Therapeutics at the ICR, said:
“We were very surprised by the specificity and strength of the link between DHX8 and HSF1. At the time we began this work, very little was known about DHX8 in human cells, and it certainly wasn’t obvious that it would play such a decisive role in regulating this key cancer‑associated pathway.
“Our research reveals an entirely new layer of control in the stress‑response machinery on which cancer cells depend. DHX8 is not just an accessory splicing factor – it appears to be indispensable for the proper processing of HSF1 and a range of other transcripts that help tumour cells survive stressful conditions.”
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. By revealing a new molecular cog in the stress‑response network, the research opens up promising new scientific territory – illustrating once again that in the microscopic world of cellular machinery, hidden players can have outsized influence.
“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. This search is already underway in our Centre for Cancer Drug Discovery, enabled by the 3D X-ray crystal structure of human DHX8 that we determined previously at the ICR.”
Image credit: MustangJoe from Pixabay
