MassIVE MSV000084838

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Proteomic analyses identify a novel role for EZH2 in the initiation of cancer cell drug tolerance

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Description

Acquisition of drug resistance remains a chief impediment to successful cancer therapy, and we previously described a transient drug-tolerant cancer cell population (DTPs) whose survival is in part dependent on the activities of the histone methyltransferases G9a/EHMT2 and EZH2, the latter being the catalytic component of the polycomb repressive complex 2 (PRC2). Here, we applied multiple proteomic techniques to better understand the role of these HMTs in the establishment of the DTP state. Proteome-wide comparisons of lysine methylation patterns revealed that DTPs have increased methylation on K116 of PRC member Jarid2, an event that helps stabilize and recruit PRC2 to chromatin. We also found that EZH2, in addition to methylating histone H3K27, also methylates G9a at K185, and that methylated G9a better recruits repressive complexes to chromatin; similar to complexes recruited by histone H3 methylated at K9. Finally, a detailed histone posttranslational modification (PTM) analysis shows that EZH2, either directly or through its ability to methylate G9a, alters H3K9 methylation in the specific context of H3 serine10 phosphorylation, and primarily in a cancer cell subpopulation that serves as DTP precursors. We also show that combinations of histone PTMs recruit a different set of complexes to chromatin, shedding light on the temporal mechanisms that contribute to drug tolerance. [doi:10.25345/C5Z97Z] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: epigenetics, chromatin, EZH2, G9a, histone, drug tolerance, cancer

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Principal Investigators:
(in alphabetical order) 		David Arnott, Genentech, Inc., United States
Submitting User: arnott
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