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

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8 Scopus citations

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 languageEnglish
Article number1756
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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© 2023, The Author(s).

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