Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis
Open Access
- 7 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (7), 980-997
- https://doi.org/10.1158/2159-8290.CD-19-0532
Abstract
Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/beta-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. SIGNIFICANCE: Oncogenic G9a abnormalities drive tumorigenesis and the "cold" immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore "hot" tumor immune microenvironments.Other Versions
Funding Information
- NIH (5P01 CA163222, 1R01CA222871, 5R01AR072304, 5R01 AR043369-22)
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Japan Society for the Promotion of Science
- NIH (R01HD088626, R01GM122749)
- Cancer Research UK (C588/A19167, C8216/A6129, C588/A10721)
- NIH (CA83115)
- Horizon 2020 (641458)
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