Affordable Access

Publisher Website

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

Authors
  • Jana, Sujata1
  • Brahma, Sandipan2
  • Arora, Sonali1
  • Wladyka, Cynthia L1
  • Hoang, Patrick1
  • Blinka, Steven3
  • Hough, Rowan1
  • Horn, Jessie L1
  • Liu, Yuzhen1
  • Wang, Li-Jie1
  • Depeille, Philippe4
  • Smith, Eric4
  • Montgomery, Robert B5
  • Lee, John K6
  • Haffner, Michael C7
  • Vakar-Lopez, Funda8
  • Grivas, Petros5
  • Wright, Jonathan L9
  • Lam, Hung-Ming9
  • Black, Peter C10
  • And 5 more
  • 1 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 2 Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 3 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • 4 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 5 Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • 6 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.
  • 7 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
  • 8 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
  • 9 Department of Urology, University of Washington, Seattle, WA 98915, USA.
  • 10 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. , (Canada)
  • 11 Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
  • 12 Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 13 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: [email protected].
Type
Published Article
Journal
Cancer cell
Publication Date
May 08, 2023
Volume
41
Issue
5
Identifiers
DOI: 10.1016/j.ccell.2023.03.021
PMID: 37084735
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times