Unknown

Dataset Information

0

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.

PROVIDER: S-EPMC6310147 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC4742734 | BioStudies
| S-EPMC6749836 | BioStudies
| S-EPMC8558507 | BioStudies
| S-EPMC5262454 | BioStudies
| S-EPMC6616564 | BioStudies
| S-EPMC6354736 | BioStudies
2018-10-03 | GSE104981 | GEO
2018-10-03 | GSE104984 | GEO
2018-10-03 | GSE104983 | GEO
2018-10-03 | GSE104985 | GEO