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

Li, F.; Wang, Y.; Hwang, I.; Janng, J.-Y.; Zhou, L.; Deng, Z.; Yu, E. Y.; Cai, Y.; Wu, C.; Han, Z.; Huang, Y.-H.; Huang, X.; Zhang, L.; Yao, J.; Lue, N.; Lieberman, P.; Ying, H.; Paik, J.; Zheng, H.

doi:10.1101/2023.02.10.528023

bioRxiv · 10.1101/2023.02.10.528023

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

Li, F.·Wang, Y.·Hwang, I.·Janng, J.-Y.·Zhou, L.·Deng, Z.·Yu, E. Y.·Cai, Y.·Wu, C.·Han, Z.·Huang, Y.-H.·Huang, X.·Zhang, L.·Yao, J.·Lue, N.·Lieberman, P.·Ying, H.·Paik, J.·Zheng, H.

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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 homology-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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Li, F., Wang, Y., Hwang, I., Janng, J.-Y., Zhou, L., Deng, Z., Yu, E. Y., Cai, Y., Wu, C., Han, Z., Huang, Y.-H., Huang, X., Zhang, L., Yao, J., Lue, N., Lieberman, P., Ying, H., Paik, J., Zheng, H.. 2023-02-11. Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance. https://doi.org/10.1101/2023.02.10.528023

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