Hinohara K, Wu HJ, Vigneau S, McDonald TO, Igarashi KJ, Yamamoto KN, Madsen T, Fassl A, Egri SB, Papanastasiou M, Ding L, Peluffo G, Cohen O, Kales SC, Lal-Nag M, Rai G, Maloney DJ, Jadhav A, Simeonov A, Wagle N, Brown M, Meissner A, Sicinski P, Jaffe JD, Jeselsohn R, Gimelbrant AA, Michor F, Polyak K. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell. 2018 Dec 10; 34(6):939-953.e9.

Citation

Hinohara K, Wu HJ, Vigneau S, McDonald TO, Igarashi KJ, Yamamoto KN, Madsen T, Fassl A, Egri SB, Papanastasiou M, Ding L, Peluffo G, Cohen O, Kales SC, Lal-Nag M, Rai G, Maloney DJ, Jadhav A, Simeonov A, Wagle N, Brown M, Meissner A, Sicinski P, Jaffe JD, Jeselsohn R, Gimelbrant AA, Michor F, Polyak K. 2018. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer cell. 34(6):939-953.e9. Pubmed: 30472020 DOI:S1535-6108(18)30480-X

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.

Related Faculty

Franziska Michor, Ph.D.

Michor Lab

Franziska Michor uses the tools of theoretical evolutionary biology, applied mathematics, statistics, and computational biology to address important questions in cancer research.

Alexander Meissner, Ph.D.

The Meissner laboratory uses genomic tools to study stem cell biology with a particular focus on epigenetic reprogramming.