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Proteomic Analyses Identify a Novel Role for EZH2 in the Initiation of Cancer Cell Drug Tolerance
journal contribution
posted on 2020-03-23, 19:33 authored by Victoria Pham, Robert Pitti, Charles A. Tindell, Tommy K. Cheung, Alexandre Masselot, Jean-Phillipe Stephan, Gulfem D. Guler, Catherine Wilson, Jennie Lill, David Arnott, Marie ClassonAcquisition
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 apply multiple proteomic techniques to
better understand the role of these histone methyltransferases (HMTs)
in the establishment of the DTP state. Proteome-wide comparisons of
lysine methylation patterns reveal that DTPs display an increase in
methylation on K116 of PRC member Jarid2, an event that helps stabilize
and recruit PRC2 to chromatin. We also find that EZH2, in addition
to methylating histone H3K27, also can methylate G9a at K185, and
that methylated G9a better recruits repressive complexes to chromatin.
These complexes are similar to complexes recruited by histone H3 methylated
at K9. Finally, a detailed histone post-translational modification
(PTM) analysis shows that EZH2, either directly or through its ability
to methylate G9a, alters H3K9 methylation in the context of H3 serine
10 phosphorylation, 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.
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Keywords
Novel RolechromatinK 116PRC 2drug resistancedrug toleranceH 3K methylationDTP precursorsHMTdrug-tolerant cancer cell populationProteome-wide comparisonsK 9.Cancer Cell Drug Tolerance AcquisitionDTP stateProteomic Analyses Identifyhistone methyltransferasescancer cell subpopulationhistone PTMsmethylating histone H 3Klysine methylation patternshistone post-translational modificationDTPs displaymethylated G 9ahistone H 3 methylatedmethylate G 9aH 3 serine 10 phosphorylationproteomic techniquescomplexhistone methyltransferases G 9aEZH 2cancer therapy
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