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 Müschen; Jun Qi; Jianjun Chen; Kevin Hiom; Alexander J. R. Bishop; Chun-Wei Chen

doi:10.1002/advs.202206584

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)

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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 language	English
Article number	e2206584
Number of pages	16
Journal	Advanced Science
Volume	10
Issue number	17
Early online date	19 Apr 2023
DOIs	https://doi.org/10.1002/advs.202206584
Publication status	Published - 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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202206584Licence: CC BY

Final Published VersionFinal published version, 10.3 MBLicence: CC BY

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Li, M., Yang, L., Chan, A. K. N., Pokharel, S. P., Liu, Q., Mattson, N., Xu, X., Chang, W.-H., Miyashita, K., Singh, P., Zhang, L., Li, M., Wu, J., Wang, J., Chen, B., Chan, L. N., Lee, J., Zhang, X. H., Rosen, S. T., ... Chen, C.-W. (2023). Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis. Advanced Science, 10(17), Article e2206584. https://doi.org/10.1002/advs.202206584

@article{1b539080cc1a4db9b0907bf0fde8a261,

title = "Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis",

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.",

keywords = "EEF1A1, epigenetic, Ewing sarcoma, KAT5, MYC, RUVBL1",

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

note = "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{\textquoteright}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: {\textcopyright} 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.",

year = "2023",

month = jun,

day = "13",

doi = "10.1002/advs.202206584",

language = "English",

volume = "10",

number = "17",

}

Li, M, Yang, L, Chan, AKN, Pokharel, SP, Liu, Q, Mattson, N, Xu, X, Chang, W-H, Miyashita, K, Singh, P, Zhang, L, Li, M, Wu, J, Wang, J, Chen, B, Chan, LN, Lee, J, Zhang, XH, Rosen, ST, Müschen, M, Qi, J, Chen, J, Hiom, K, Bishop, AJR & Chen, C-W 2023, 'Epigenetic control of translation checkpoint and tumor progression via RUVBL1-EEF1A1 axis', Advanced Science, vol. 10, no. 17, e2206584. https://doi.org/10.1002/advs.202206584

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 - http://www.scopus.com/inward/record.url?scp=85152911206&partnerID=8YFLogxK

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 -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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