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Clarke TL, Tang R, Chakraborty D, Van Rechem C, Ji F, Mishra S, Ma A, Kaniskan HU, Jin J, Lawrence MS, Sadreyev RI, Whetstine JR
Histone Lysine Methylation Dynamics Control EGFR DNA Copy Number Amplification
Cancer Discov (2020) 10:306-325.
Abstract
Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMTs) and demethylases (KDMs) in regulating transient site-specific DNA copy number gains (TSSGs). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance in order to control extrachromosomal amplification of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and epidermal growth factor) are able to directly promote EGFR amplification through modulation of the enzymes controlling EGFR copy gains. Moreover, we demonstrate that chemical inhibitors targeting specific KMTs and KDMs are able to promote or block extrachromosomal EGFR amplification, which identifies potential therapeutic strategies for controlling EGFR copy number heterogeneity in cancer, and in turn, drug response.
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Publication Date: 2020-11-27.
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Last updated on Thursday, April 02, 2020