Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis

Mingli Li, Lu Yang, Anthony K. N. Chan, Sheela Pangeni Pokharel, Qiao Liu, Nicole Mattson, Xiaobao Xu, Wen-Han Chang, Kazuya Miyashita, Priyanka Singh, Leisi Zhang, Maggie Li, Jun Wu, Jinhui Wang, Bryan Chen, Lai N. Chan, Jaewoong Lee, Xu Hannah Zhang, Steven T. Rosen, Markus MüschenJun Qi, Jianjun Chen, Kevin Hiom, Alexander J. R. Bishop, Chun-Wei Chen (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
68 Downloads (Pure)

Abstract

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

Original languageEnglish
Article numbere2206584
Number of pages16
JournalAdvanced Science
Volume10
Issue number17
Early online date19 Apr 2023
DOIs
Publication statusPublished - 13 Jun 2023

Keywords

  • EEF1A1
  • epigenetic
  • Ewing sarcoma
  • KAT5
  • MYC
  • RUVBL1

ASJC Scopus subject areas

  • General Engineering
  • General Physics and Astronomy
  • General Chemical Engineering
  • General Materials Science
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Medicine (miscellaneous)

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