期刊
CANCER DISCOVERY
卷 10, 期 2, 页码 306-325出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0463
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资金
- NIH/NCI Cancer Center Support Grant [P30 CA006927]
- NIH [P30 DK040561, R01GM122749]
- EMBO long-term fellowship [EMBO ALTF 449-2017]
- Senior Research Training Fellowship from the American Lung Association
- MGH ECOR Tosteson Postdoctoral Training Fellowship
- Ovarian Cancer Research Fund Alliance (Ann and Sol Schreiber Mentored Investigator Award) [543667]
- [R01GM097360]
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 (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplification of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and EGF) 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. SIGNIFICANCE This study identifies a network of epigenetic factors and cellular signals that directly control EGFR DNA amplification. We demonstrate that chemical inhibitors targeting enzymes controlling this amplification can be used to rheostat EGFR copy number, which uncovers therapeutic opportunities for controlling EGFR DNA amplification heterogeneity and the associated drug response.
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