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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

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

doi

10.1016/j.ccell.2018.10.014

subject

Has Abstract

pub_date

2018-12-10 00:00:00

pages

939-953.e9

issue

6

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(18)30480-X

journal_volume

34

pub_type

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