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

TY - JOUR

T1 - Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis

AU - Li, Mingli

AU - Yang, Lu

AU - Chan, Anthony K. N.

AU - Pokharel, Sheela Pangeni

AU - Liu, Qiao

AU - Mattson, Nicole

AU - Xu, Xiaobao

AU - Chang, Wen-Han

AU - Miyashita, Kazuya

AU - Singh, Priyanka

AU - Zhang, Leisi

AU - Li, Maggie

AU - Wu, Jun

AU - Wang, Jinhui

AU - Chen, Bryan

AU - Chan, Lai N.

AU - Lee, Jaewoong

AU - Zhang, Xu Hannah

AU - Rosen, Steven T.

AU - Müschen, Markus

AU - Qi, Jun

AU - Chen, Jianjun

AU - Hiom, Kevin

AU - Bishop, Alexander J. R.

AU - Chen, Chun-Wei

N1 - Funding Information: This work was supported by the Sarcoma Foundation of America SFA 05-22 (to M.L.), American Society of Hematology (to C.W.C.), Alex’s Lemonade Stand Foundation 18-11849 (to C.W.C.), Leukemia & Lymphoma Society (to J.C. and S.T.R.), Stand Up To Cancer & Cancer Research UK #RT617 (to A.J.R.B., K.H. and C.W.C.), and National Institutes of Health Grants CA233691, CA236626, CA278050 (to C.W.C.), CA233922 (to S.T.R), and CA211614, CA243386 (to J.C.). The sequencing and structural computational studies were supported by the National Institutes of Health P30 award CA033572 (City of Hope). Copyright: © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

PY - 2023/6/13

Y1 - 2023/6/13

N2 - 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.

AB - 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.

KW - EEF1A1

KW - epigenetic

KW - Ewing sarcoma

KW - KAT5

KW - MYC

KW - RUVBL1

UR - https://www.scopus.com/pages/publications/85152911206

U2 - 10.1002/advs.202206584

DO - 10.1002/advs.202206584

M3 - Article

C2 - 37075745

SN - 2198-3844

VL - 10

JO - Advanced Science

JF - Advanced Science

IS - 17

M1 - e2206584

ER -