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

Producción científica: Articlerevisión exhaustiva

10 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Número de artículo2206584
PublicaciónAdvanced Science
Volumen10
N.º17
DOI
EstadoPublished - jun 13 2023

ASJC Scopus subject areas

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

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