GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility

Dawn Sijin Nin; Caryn Wujanto; Tuan Zea Tan; Diana Lim; J Mirjam A Damen; Kuan-Yi Wu; Ziyu Melvin Dai; Zheng-Wei Lee; Shabana Binte Idres; Yiat Horng Leong; Sudhakar Jha; Joseph Soon-Yau Ng; Jeffrey J H Low; Shih-Chung Chang; David Shao Peng Tan; Wei Wu; Bok Ai Choo; Lih-Wen Deng

doi:10.1016/j.celrep.2021.109621

GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility

Dawn Sijin Nin, Caryn Wujanto, Tuan Zea Tan, Diana Lim, J Mirjam A Damen, Kuan-Yi Wu, Ziyu Melvin Dai, Zheng-Wei Lee, Shabana Binte Idres, Yiat Horng Leong, Sudhakar Jha, Joseph Soon-Yau Ng, Jeffrey J H Low, Shih-Chung Chang, David Shao Peng Tan, Wei Wu, Bok Ai Choo, Lih-Wen Deng

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

Original language	English
Article number	109621
Pages (from-to)	1-26
Number of pages	26
Journal	Cell Reports
Volume	36
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2021.109621
Publication status	Published - 31 Aug 2021

Keywords

CT antigens
DNA damage response
DNA repair
GAGE
GAGE12
cancer testis antigens
cervical cancer
chromatin dynamics
radioresistance
radiotherapy

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Nin, D. S., Wujanto, C., Tan, T. Z., Lim, D., Damen, J. M. A., Wu, K.-Y., Dai, Z. M., Lee, Z.-W., Idres, S. B., Leong, Y. H., Jha, S., Ng, J. S.-Y., Low, J. J. H., Chang, S.-C., Tan, D. S. P., Wu, W., Choo, B. A., & Deng, L.-W. (2021). GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility. Cell Reports, 36(9), 1-26. Article 109621. https://doi.org/10.1016/j.celrep.2021.109621

@article{7b84d5e2420c4c9bbeeb07efba87696a,

title = "GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility",

abstract = "Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.",

keywords = "CT antigens, DNA damage response, DNA repair, GAGE, GAGE12, cancer testis antigens, cervical cancer, chromatin dynamics, radioresistance, radiotherapy",

author = "Nin, {Dawn Sijin} and Caryn Wujanto and Tan, {Tuan Zea} and Diana Lim and Damen, {J Mirjam A} and Kuan-Yi Wu and Dai, {Ziyu Melvin} and Zheng-Wei Lee and Idres, {Shabana Binte} and Leong, {Yiat Horng} and Sudhakar Jha and Ng, {Joseph Soon-Yau} and Low, {Jeffrey J H} and Shih-Chung Chang and Tan, {David Shao Peng} and Wei Wu and Choo, {Bok Ai} and Lih-Wen Deng",

note = "Funding Information: This work was supported by grants from the Terry Fox Foundation Singapore ( NF15TFR051 ) to B.A.C., National University Hospital, Singapore, Junior Pitch for Fund to C.W., National University Health System, Singapore ( R-183-000-461-733 ) to D.S.N., and the Ministry of Education, Taiwan ; ( MOE-AcRF-Tier 2 and R-183-000-459-112 ) and National University Cancer Institute, Singapore ( NR15NMR229 and NR18NMR119 ) to L.-W.D. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = aug,

day = "31",

doi = "10.1016/j.celrep.2021.109621",

language = "English",

volume = "36",

pages = "1--26",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier Saunders",

number = "9",

}

Nin, DS, Wujanto, C, Tan, TZ, Lim, D, Damen, JMA, Wu, K-Y, Dai, ZM, Lee, Z-W, Idres, SB, Leong, YH, Jha, S, Ng, JS-Y, Low, JJH, Chang, S-C, Tan, DSP, Wu, W, Choo, BA & Deng, L-W 2021, 'GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility', Cell Reports, vol. 36, no. 9, 109621, pp. 1-26. https://doi.org/10.1016/j.celrep.2021.109621

TY - JOUR

T1 - GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility

AU - Nin, Dawn Sijin

AU - Wujanto, Caryn

AU - Tan, Tuan Zea

AU - Lim, Diana

AU - Damen, J Mirjam A

AU - Wu, Kuan-Yi

AU - Dai, Ziyu Melvin

AU - Lee, Zheng-Wei

AU - Idres, Shabana Binte

AU - Leong, Yiat Horng

AU - Jha, Sudhakar

AU - Ng, Joseph Soon-Yau

AU - Low, Jeffrey J H

AU - Chang, Shih-Chung

AU - Tan, David Shao Peng

AU - Wu, Wei

AU - Choo, Bok Ai

AU - Deng, Lih-Wen

N1 - Funding Information: This work was supported by grants from the Terry Fox Foundation Singapore ( NF15TFR051 ) to B.A.C., National University Hospital, Singapore, Junior Pitch for Fund to C.W., National University Health System, Singapore ( R-183-000-461-733 ) to D.S.N., and the Ministry of Education, Taiwan ; ( MOE-AcRF-Tier 2 and R-183-000-459-112 ) and National University Cancer Institute, Singapore ( NR15NMR229 and NR18NMR119 ) to L.-W.D. Publisher Copyright: © 2021 The Author(s)

PY - 2021/8/31

Y1 - 2021/8/31

N2 - Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

AB - Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

KW - CT antigens

KW - DNA damage response

KW - DNA repair

KW - GAGE

KW - GAGE12

KW - cancer testis antigens

KW - cervical cancer

KW - chromatin dynamics

KW - radioresistance

KW - radiotherapy

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U2 - 10.1016/j.celrep.2021.109621

DO - 10.1016/j.celrep.2021.109621

M3 - Article

C2 - 34469741

SN - 2211-1247

VL - 36

SP - 1

EP - 26

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 109621

ER -

GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility

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Keywords

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