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Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1-EEF1A1 Axis

Mingli Li1, Lu Yang1,2, Anthony K N Chan1,2

  • 1Department of Systems Biology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 19, 2023
PubMed

Insights

Researchers identified RUVBL1 as crucial for Ewing sarcoma progression by regulating MYC signaling and protein synthesis. Suppressing RUVBL1 shows promise for combination cancer therapy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic dysregulation is implicated in various cancers, including Ewing sarcoma (EwS).
  • The specific epigenetic mechanisms driving oncogenic signaling and treatment response in EwS are not fully understood.

Purpose of the Study:

  • To elucidate the epigenetic networks essential for Ewing sarcoma tumor progression and therapeutic response.
  • To identify key regulators of oncogenic signaling and protein synthesis in EwS.

Main Methods:

  • Utilized epigenetics- and complex-focused CRISPR screens to identify essential genes in EwS.
  • Performed CRISPR gene body scans to pinpoint critical functional residues.
  • Investigated the effects of RUVBL1 suppression on MYC signaling, histone acetylation, and protein synthesis.
  • Evaluated combination therapy strategies in EwS models.

Main Results:

  • RUVBL1, a component of the NuA4 complex, was identified as essential for EwS tumor growth.
  • RUVBL1 suppression led to reduced tumor growth, decreased histone H4 acetylation, and diminished MYC signaling.
  • RUVBL1 was found to regulate MYC chromatin binding and MYC-driven EEF1A1 expression, impacting protein synthesis.
  • Synergistic effects were observed between RUVBL1 suppression and MYC inhibition in EwS models.

Conclusions:

  • RUVBL1 plays a critical role in maintaining oncogenic signaling and tumor progression in Ewing sarcoma.
  • Targeting the interplay between chromatin remodelers, MYC, and protein translation offers a novel therapeutic strategy for EwS.
  • Combination therapy involving RUVBL1 suppression and MYC inhibition demonstrates therapeutic potential for Ewing sarcoma.
Keywords:
EEF1A1Ewing sarcomaKAT5MYCRUVBL1epigenetic

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