Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance

Fei Li; Yizhe Wang; Inah Hwang; Ja Young Jang; Libo Xu; Zhong Deng; Eun Young Yu; Yiming Cai; Caizhi Wu; Zhenbo Han; Yu Han Huang; Xiangao Huang; Ling Zhang; Jun Yao; Neal F. Lue; Paul M. Lieberman; Haoqiang Ying; Jihye Paik; Hongwu Zheng

doi:10.1038/s41467-023-37480-2

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance

Fei Li, Yizhe Wang, Inah Hwang, Ja Young Jang, Libo Xu, Zhong Deng, Eun Young Yu, Yiming Cai, Caizhi Wu, Zhenbo Han, Yu Han Huang, Xiangao Huang, Ling Zhang, Jun Yao, Neal F. Lue, Paul M. Lieberman, Haoqiang Ying, Jihye Paik, Hongwu Zheng

Pharmaceutical Sciences

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

Abstract

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% − 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

Original language	English
Article number	1756
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37480-2
State	Published - Dec 2023

Bibliographical note

Funding Information:
This work was partly supported by a research award from the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital. Additional funding was provided to J. Paik by NIH/NCI grant P01 #CA214274. J-Y. Jang is partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2021R1A6A3A03039136). H. Zheng was partly supported by the Sontag Foundation and the Chen & Xiao AntiCancer Foundation.

Publisher Copyright:
© 2023, The Author(s).

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Li, F., Wang, Y., Hwang, I., Jang, J. Y., Xu, L., Deng, Z., Yu, E. Y., Cai, Y., Wu, C., Han, Z., Huang, Y. H., Huang, X., Zhang, L., Yao, J., Lue, N. F., Lieberman, P. M., Ying, H., Paik, J., & Zheng, H. (2023). Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance. Nature Communications, 14(1), Article 1756. https://doi.org/10.1038/s41467-023-37480-2

@article{d15c208d0f7d482899fe8e8a4f5543ca,

title = "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance",

abstract = "Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% − 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.",

author = "Fei Li and Yizhe Wang and Inah Hwang and Jang, {Ja Young} and Libo Xu and Zhong Deng and Yu, {Eun Young} and Yiming Cai and Caizhi Wu and Zhenbo Han and Huang, {Yu Han} and Xiangao Huang and Ling Zhang and Jun Yao and Lue, {Neal F.} and Lieberman, {Paul M.} and Haoqiang Ying and Jihye Paik and Hongwu Zheng",

note = "Funding Information: This work was partly supported by a research award from the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital. Additional funding was provided to J. Paik by NIH/NCI grant P01 #CA214274. J-Y. Jang is partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2021R1A6A3A03039136). H. Zheng was partly supported by the Sontag Foundation and the Chen & Xiao AntiCancer Foundation. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-37480-2",

language = "English",

volume = "14",

journal = "Nature Communications",

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Li, F, Wang, Y, Hwang, I, Jang, JY, Xu, L, Deng, Z, Yu, EY, Cai, Y, Wu, C, Han, Z, Huang, YH, Huang, X, Zhang, L, Yao, J, Lue, NF, Lieberman, PM, Ying, H, Paik, J & Zheng, H 2023, 'Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance', Nature Communications, vol. 14, no. 1, 1756. https://doi.org/10.1038/s41467-023-37480-2

TY - JOUR

T1 - Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance

AU - Li, Fei

AU - Wang, Yizhe

AU - Hwang, Inah

AU - Jang, Ja Young

AU - Xu, Libo

AU - Deng, Zhong

AU - Yu, Eun Young

AU - Cai, Yiming

AU - Wu, Caizhi

AU - Han, Zhenbo

AU - Huang, Yu Han

AU - Huang, Xiangao

AU - Zhang, Ling

AU - Yao, Jun

AU - Lue, Neal F.

AU - Lieberman, Paul M.

AU - Ying, Haoqiang

AU - Paik, Jihye

AU - Zheng, Hongwu

N1 - Funding Information: This work was partly supported by a research award from the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital. Additional funding was provided to J. Paik by NIH/NCI grant P01 #CA214274. J-Y. Jang is partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2021R1A6A3A03039136). H. Zheng was partly supported by the Sontag Foundation and the Chen & Xiao AntiCancer Foundation. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% − 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

AB - Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% − 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

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DO - 10.1038/s41467-023-37480-2

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

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ER -

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance

Abstract

Bibliographical note

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