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Cancer Cell DOI:10.1016/j.ccell.2018.10.014

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

Publication TypeJournal Article
Year of Publication2018
AuthorsHinohara, K, Wu, H-J, 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
JournalCancer Cell
Volume34
Issue6
Pages939-953.e9
Date Published2018 Dec 10
ISSN1878-3686
KeywordsBreast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Estradiol, Estrogen Receptor Modulators, Female, Fulvestrant, Genetic Heterogeneity, Humans, Jumonji Domain-Containing Histone Demethylases, MCF-7 Cells, Nuclear Proteins, Repressor Proteins, Retinoblastoma-Binding Protein 2, Transcriptome, Whole Exome Sequencing
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.

DOI10.1016/j.ccell.2018.10.014
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30472020?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID30472020
PubMed Central IDPMC6310147
Grant ListR35 CA197623 / CA / NCI NIH HHS / United States
P01 CA080111 / CA / NCI NIH HHS / United States
R01 CA202634 / CA / NCI NIH HHS / United States
U54 HG008097 / HG / NHGRI NIH HHS / United States
U54 CA193461 / CA / NCI NIH HHS / United States