MassIVE MSV000096930

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GRHL2 methylation links KDM4C activity to cathepsin L-mediated histone H3 cleavage

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Description

Basal breast cancer is a subtype with inferior prognosis necessitating novel therapeutic targets. Here, we describe a unique role for the KDM4C histone lysine demethylase in KDM4C-amplified basal breast cancers, where KDM4C inhibition triggers chromatin and transcriptomic remodeling without substantial changes of its canonical substrates H3K9me3 and H3K36me3. Rather KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL) resulting in decreased glutamate-cysteine ligase expression and increased reactive oxygen species (ROS). CTSL is recruited to the chromatin by the GRHL2 transcription factor that is methylated at lysine 453 following KDM4C inhibition triggering CTSL histone clipping activity. Deletion of CTSL or inhibition of ROS rescued KDM4-loss-mediated tumor suppression. Our study reveals a novel function for KDM4C that links cellular redox regulation to chromatin remodeling. [doi:10.25345/C5319SF4G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: global chromatin profiling, histone clipping, cathepsin L ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: malpap1
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