| Literature DB >> 30472020 |
Kunihiko Hinohara1, Hua-Jun Wu2, Sébastien Vigneau3, Thomas O McDonald4, Kyomi J Igarashi3, Kimiyo N Yamamoto2, Thomas Madsen2, Anne Fassl3, Shawn B Egri5, Malvina Papanastasiou5, Lina Ding1, Guillermo Peluffo1, Ofir Cohen6, Stephen C Kales7, Madhu Lal-Nag7, Ganesha Rai7, David J Maloney7, Ajit Jadhav7, Anton Simeonov7, Nikhil Wagle8, Myles Brown9, Alexander Meissner10, Piotr Sicinski3, Jacob D Jaffe5, Rinath Jeselsohn1, Alexander A Gimelbrant3, Franziska Michor11, Kornelia Polyak12.
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.Entities:
Keywords: KDM5B; acquired resistance; barcoding; cellular heterogeneity; endocrine resistance; epigenetic; pre-existing resistance; single-cell RNA-seq; subclonal fraction; transcriptomic heterogeneity
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Year: 2018 PMID： 30472020 PMCID： PMC6310147 DOI： 10.1016/j.ccell.2018.10.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743