Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression - Archive ouverte HAL
Article Dans Une Revue Cancer Cell Année : 2023

Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression

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We uncover a tumor-suppressive process in urothelium called transcriptional-translational conflict caused by deregulation of the central chromatin remodeling component ARID1A. Loss of Arid1a triggers an increase in a nexus of pro-proliferation transcripts, but a simultaneous inhibition of the eukaryotic elongation factor 2 (eEF2), which results in tumor suppression. Resolution of this conflict through enhancing translation elongation speed enables the efficient and precise synthesis of a network of poised mRNAs resulting in uncontrolled proliferation, clonogenic growth, and bladder cancer progression. We observe a similar phenomenon in patients with ARID1A-low tumors, which also exhibit increased translation elongation activity through eEF2. These findings have important clinical implications because ARID1A-deficient, but not ARID1A-proficient, tumors are sensitive to pharmacologic inhibition of protein synthesis. These discoveries reveal an oncogenic stress created by transcriptional-translational conflict and provide a unified gene expression model that unveils the importance of the crosstalk between transcription and translation in promoting cancer.
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hal-04603609 , version 1 (06-06-2024)

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Sujata Jana, Sandipan Brahma, Sonali Arora, Cynthia Wladyka, Patrick Hoang, et al.. Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression. Cancer Cell, 2023, 41 (5), pp.853-870.e13. ⟨10.1016/j.ccell.2023.03.021⟩. ⟨hal-04603609⟩
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