Journal Article

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

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

2023

Overview

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. Dysregulation of MYC family proto‐oncogene is a hallmark of tumorigenesis in various cancers. This study demonstrates that RUVBL1 is a critical modulator of MYC‐mediated EEF1A1 expression and protein synthesis. RUVBL1 serves as a master regulator of oncogenic MYC signaling via controlling MYC chromatin binding. Targeting RUVBL1 synergizes with the pharmacological targeting of MYC, pointing toward a more effective combinatorial therapy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Apoptosis / ATPases Associated with Diverse Cellular Activities - genetics / ATPases Associated with Diverse Cellular Activities - metabolism / Carrier Proteins - genetics / Cell cycle / Cell Line, Tumor / Chromatin / CRISPR / DNA Helicases - genetics / DNA Helicases - metabolism / EEF1A1 / Epigenesis, Genetic - genetics / epigenetic / Epigenetics / Ewing sarcoma / Ewings sarcoma / Genes / Humans / KAT5 / Medical prognosis / MYC / Peptide Elongation Factor 1 - genetics / Peptide Elongation Factor 1 - metabolism / Peptide Elongation Factor 1 - therapeutic use / Proteins / Proto-Oncogene Protein c-fli-1 - genetics / Proto-Oncogene Proteins c-myc - metabolism / RNA-Binding Protein EWS - genetics / RUVBL1 / Sarcoma, Ewing - genetics / Signal Transduction - genetics / Transcription factors / Tumors