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

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.

SUBMITTER: Hinohara K

PROVIDER: S-EPMC6310147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Kdm5/Lid Regulates Chromosome Architecture in Meiotic Prophase I Independently of Its Histone Demethylase Activity.

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KDM5B links cellular transcriptome heterogeneity to therapy resistance

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-10-03 | GSE104988 | GEO

KDM5B links cellular transcriptome heterogeneity to therapy resistance (inDrop)

Project description:The KDM5B histone H3 lysine 4 (H3K4) demethylase has been implicated in therapy resistance in multiple cancer types including breast cancer, but the underlying mechanism is poorly defined. Here we show that inhibition of KDM5B activity increases sensitivity to anti-estrogens by modulating estrogen-receptor (ER) signaling. Conversely, acquired resistance to KDM5 inhibitors leads to gain of ER chromatin binding and estrogen-independent growth. Sequencing of barcoded cell populations and mathematical modeling demonstrate selection for pre-existent genetically distinct endocrine-resistant cells, while resistance to KDM5 inhibitors is a switch to an acquired epigenetic state. Rare resistant cells can already be detected by single cell RNA-seq prior to treatment. Inhibition of KDM5B in luminal ER+ cells increases H3K4me3 broad domains at promoters and decreases cellular transcriptional heterogeneity. Higher transcriptome heterogeneity is associated with higher KDM5B levels and poor prognosis in ER+ luminal breast tumors.

2018-10-03 | GSE104987 | GEO

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