Transcriptional–Translational Conflict Hinders Bladder Oncogenesis

ATP-dependent SWI/SNF family nucleosome remodeling complexes are recurrently mutated in human cancers, and in bladder cancer, 25% of patients exhibit loss-of-function mutations in the tumor suppressor gene ARID1A, which encodes a central component of multiple SWI/SNF complexes. To understand the impact of ARID1A loss on gene expression in the bladder, Jana and colleagues utilized genetic mouse models in which Arid1a was conditionally deleted in multiple tissues or basal cells. Analysis of basal urothelial cells from wild-type or Arid1a^fl/fl bladders revealed that Arid1a loss induced the mRNA expression of multiple cancer drivers and regulators of cell proliferation, including Aurkb, Igf2, and Fgfr3, while concomitantly decreasing de novo protein synthesis, suggesting that the loss of Arid1a leads to transcriptional–translational conflict of specific ARID1A target genes, which may explain why Arid1a^fl/fl mice did not develop tumors. Arid1a loss decreased the activity of the translation elongation regulator eEF2 by increasing eEF2 kinase (eEF2K)–mediated eEF2 phosphorylation, and Eef2k deletion was sufficient to restore protein synthesis, promote replicative mortality, and induce uncontrolled cell growth in Arid1a^fl/fl bladders. Arid1a loss contributed to elevated eEF2K activity through accumulation of trimethylation of lysine 27 of histone 3 at the promoter of Rasgrp1, a gene that encodes a RAS guanine nucleotide exchange factor, resulting in decreased MAP kinase–dependent inactivation of eEF2K. In line with these findings, patients with ARID1A-low tumors exhibited enhanced translation elongation, suggesting that overcoming transcriptional–translational conflict is necessary to unleash the oncogenic properties of ARID1A loss. Notably, pharmacologic inhibition of translation initiation specifically reduced the viability of ARID1A-deficient but not ARID1A-proficient human bladder cancer cell lines in vitro and reduced tumor growth and increased apoptosis of ARID1A-low patient-derived xenografts in vivo, demonstrating that induction of transcriptional–translational conflict may have therapeutic potential. Together, these findings shed light on a tumor-suppressive process in which transcriptional–translational conflict prevents cancer transformation and highlight a therapeutic vulnerability of ARID1A-low deficient bladder cancers.

Jana S, Brahma S, Arora S, Wladyka CL, Hoang P, Blinka S, et al. Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression. Cancer Cell 2023;41:853–70.e13.

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