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Cancer Discovery
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Research Articles

An Epigenetic Mechanism Underlying Chromosome 17p Deletion–Driven Tumorigenesis

Mei Chen, Xuelan Chen, Shujun Li, Xiangyu Pan, Yanqiu Gong, Jianan Zheng, Jing Xu, Chengjian Zhao, Qi Zhang, Shan Zhang, Lu Qi, Zhongwang Wang, Kaidou Shi, Bi-Sen Ding, Zhihong Xue, Lu Chen, Shengyong Yang, Yuan Wang, Ting Niu, Lunzhi Dai, Scott W. Lowe, Chong Chen and Yu Liu
Mei Chen
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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  • ORCID record for Mei Chen
Xuelan Chen
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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  • ORCID record for Xuelan Chen
Shujun Li
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Xiangyu Pan
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Yanqiu Gong
2Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Jianan Zheng
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Jing Xu
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Chengjian Zhao
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Qi Zhang
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Shan Zhang
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Lu Qi
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Zhongwang Wang
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Kaidou Shi
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Bi-Sen Ding
3Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
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Zhihong Xue
3Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
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Lu Chen
3Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
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Shengyong Yang
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Yuan Wang
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Ting Niu
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Lunzhi Dai
2Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Scott W. Lowe
4Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
5Howard Hughes Medical Institute, New York, New York.
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Chong Chen
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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  • For correspondence: chongchen@scu.edu.cn yuliuscu@scu.edu.cn
Yu Liu
1Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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  • For correspondence: chongchen@scu.edu.cn yuliuscu@scu.edu.cn
DOI: 10.1158/2159-8290.CD-20-0336 Published January 2021
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Abstract

Chromosome copy-number variations are a hallmark of cancer. Among them, the prevalent chromosome 17p deletions are associated with poor prognosis and can promote tumorigenesis more than TP53 loss. Here, we use multiple functional genetic strategies and identify a new 17p tumor suppressor gene (TSG), plant homeodomain finger protein 23 (PHF23). Its deficiency impairs B-cell differentiation and promotes immature B-lymphoblastic malignancy. Mechanistically, we demonstrate that PHF23, an H3K4me3 reader, directly binds the SIN3–HDAC complex through its N-terminus and represses its deacetylation activity on H3K27ac. Thus, the PHF23–SIN3–HDAC (PSH) complex coordinates these two major active histone markers for the activation of downstream TSGs and differentiation-related genes. Furthermore, dysregulation of the PSH complex is essential for the development and maintenance of PHF23-deficient and 17p-deleted tumors. Hence, our study reveals a novel epigenetic regulatory mechanism that contributes to the pathology of 17p-deleted cancers and suggests a susceptibility in this disease.

Significance: We identify PHF23, encoding an H3K4me3 reader, as a new TSG on chromosome 17p, which is frequently deleted in human cancers. Mechanistically, PHF23 forms a previously unreported histone-modifying complex, the PSH complex, which regulates gene activation through a synergistic link between H3K4me3 and H3K27ac.

This article is highlighted in the In This Issue feature, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2021;11:194–207

  • Received March 19, 2020.
  • Revision received July 19, 2020.
  • Accepted September 22, 2020.
  • Published first September 25, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 11 (1)
January 2021
Volume 11, Issue 1
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An Epigenetic Mechanism Underlying Chromosome 17p Deletion–Driven Tumorigenesis
Mei Chen, Xuelan Chen, Shujun Li, Xiangyu Pan, Yanqiu Gong, Jianan Zheng, Jing Xu, Chengjian Zhao, Qi Zhang, Shan Zhang, Lu Qi, Zhongwang Wang, Kaidou Shi, Bi-Sen Ding, Zhihong Xue, Lu Chen, Shengyong Yang, Yuan Wang, Ting Niu, Lunzhi Dai, Scott W. Lowe, Chong Chen and Yu Liu
Cancer Discov January 1 2021 (11) (1) 194-207; DOI: 10.1158/2159-8290.CD-20-0336

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An Epigenetic Mechanism Underlying Chromosome 17p Deletion–Driven Tumorigenesis
Mei Chen, Xuelan Chen, Shujun Li, Xiangyu Pan, Yanqiu Gong, Jianan Zheng, Jing Xu, Chengjian Zhao, Qi Zhang, Shan Zhang, Lu Qi, Zhongwang Wang, Kaidou Shi, Bi-Sen Ding, Zhihong Xue, Lu Chen, Shengyong Yang, Yuan Wang, Ting Niu, Lunzhi Dai, Scott W. Lowe, Chong Chen and Yu Liu
Cancer Discov January 1 2021 (11) (1) 194-207; DOI: 10.1158/2159-8290.CD-20-0336
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