KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

Paradigms and Technologies
Therapeutic Approaches

Abstract

Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.

Authors

Hinohara, Kunihiko; Wu, Hua-Jun; Vigneau, Sébastien; McDonald, Thomas O; Igarashi, Kyomi J; Yamamoto, Kimiyo N; Madsen, Thomas; Fassl, Anne; Egri, Shawn B; Papanastasiou, Malvina; Ding, Lina; Peluffo, Guillermo; Cohen, Ofir; Kales, Stephen; Lal-Nag, Madhu; Rai Bantukallu, Ganesha; Maloney, David J; Jadhav, Ajit; Simeonov, Anton; Wagle, Nikhil; Brown, Myles; Meissner, Alexander; Sicinski, Piotr; Jaffe, Jacob D; Jeselsohn, Rinath; Gimelbrant, Alexander A; Michor, Franziska; Polyak, Kornelia;

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