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Transcriptional-translational conflict prevents tumour progression in bladder cancer

The process of transcriptional-translational conflict has been defined in a recent paper, published in Cancer Cell. This represents a new molecular process that is tumour suppressive and can protect bladder epithelial cells from malignant transformation.

Tumour suppressors and translation

Major tumour suppressors, including TP53 and PTEN, have been found to be negative regulators of mRNA translation. Downregulation of these tumour-suppressor genes (TSGs) therefore leads to an increase in mRNA translation and enables cancer pathogenesis through the upregulation of oncogenic gene networks.

Recent pan-cancer genome sequencing has revealed a new class of TSGs involved in chromatin remodelling. AT-rich interactive domain-containing protein 1A (ARID1A) was found to be the most frequently mutated TSG within this new class. Deletion of ARID1A leads to transcriptional activation of oncogenic mRNA, impairments in double-strand DNA break repair and tumour progression. Although these functions confirm ARID1A as a TSG, results were lacking as to how it regulates protein synthesis in normal tissue.

Transcriptional-translational tug-of-war

In the current study, researchers from Fred Hutchinson Cancer Center (Seattle, USA) explored the deletion of ARID1A in the bladder epithelium (the urothelium). A new relationship between ARID1A and mRNA translation was uncovered, challenging the previous theory that tumour suppressors inhibit protein synthesis. The researchers named this relationship “transcriptional-translational conflict” as it shows the molecular conflict between DNA transcription and mRNA translation in the urothelium (see Figure 1).

Figure 1: Transcriptional-translational conflict in bladder urothelium. Taken from Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression (Jana et al., 2023).

The deletion of ARID1A promoted the transcription of potentially oncogenic genes. However, this was found to be countered by a decrease in translational elongation rates. This resulted in the so-called transcriptional-translational conflict, which restrains the synthesis of pro-proliferation and mitogenic proteins and collateral DNA damage response genes. Transcriptional-translational conflict therefore prevented uncontrolled cell growth and cancer progression.

Applying the conflict to other cancer types

Lead author of the study, Andrew Hsieh stated: “This work shows that there is a dynamic interplay between transcription and translation that’s actually functional and this is the first, we think, of many examples that will be discovered”.

ARID1A appears to have tumour suppressor function in other tissues, such as ovary and liver. Hseih’s team is continuing to explore the phenomenon and the potential importance of translation in cancer. “The paper really expands our understanding of basic cancer biology, but also it provides a potential therapeutic window — or a deeper understanding — of how we could use this genomic alteration (in ARID1A) as a foothold for treating patients with advanced disease”.