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.
Cancer cell. 2023 Apr 13 [Epub ahead of print]
Sujata Jana, Sandipan Brahma, Sonali Arora, Cynthia L Wladyka, Patrick Hoang, Steven Blinka, Rowan Hough, Jessie L Horn, Yuzhen Liu, Li-Jie Wang, Philippe Depeille, Eric Smith, Robert B Montgomery, John K Lee, Michael C Haffner, Funda Vakar-Lopez, Petros Grivas, Jonathan L Wright, Hung-Ming Lam, Peter C Black, Jeroen P Roose, Alexey G Ryazanov, Arvind R Subramaniam, Steven Henikoff, Andrew C Hsieh
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA., Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA., Department of Medicine, University of Washington, Seattle, WA 98195, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Department of Urology, University of Washington, Seattle, WA 98915, USA., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA., Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Genome Sciences, University of Washington, Seattle, WA 98915, USA. Electronic address: .