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 () and Hongwu Zheng ()
Additional contact information
Fei Li: Southwest Hospital
Yizhe Wang: Weill Cornell Medicine
Inah Hwang: Weill Cornell Medicine
Ja-Young Jang: Weill Cornell Medicine
Libo Xu: Cold Spring Harbor Laboratory
Zhong Deng: The Wistar Institute
Eun Young Yu: Weill Cornell Medicine
Yiming Cai: The University of Texas M. D. Anderson Cancer Center
Caizhi Wu: Cold Spring Harbor Laboratory
Zhenbo Han: The University of Texas M. D. Anderson Cancer Center
Yu-Han Huang: Cold Spring Harbor Laboratory
Xiangao Huang: Weill Cornell Medicine
Ling Zhang: Cold Spring Harbor Laboratory
Jun Yao: The University of Texas M. D. Anderson Cancer Center
Neal F. Lue: Weill Cornell Medicine
Paul M. Lieberman: The Wistar Institute
Haoqiang Ying: The University of Texas M. D. Anderson Cancer Center
Jihye Paik: Weill Cornell Medicine
Hongwu Zheng: Weill Cornell Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37480-2

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