Epigenetic regulators are attractive anticancer targets, but the promise of therapeutic strategies inhibiting some of these factors has not been proven in vivo or taken into account tumor cell heterogeneity. Here we show that the histone methyltransferase G9a, reported to be a therapeutic target in many cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs). Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by de-repressing genes which regulate the extracellular matrix. Depletion of G9a during tumorigenesis enriches tumors in TPCs and accelerates disease progression metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and targeting the histone demethylases is a more suitable approach for lung cancer treatment. Understanding cellular context and specific tumor populations is critical when targeting epigenetic regulators in cancer for future therapeutic development.
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This work was supported in part by the IASLC Young Investigator Fellowship (S.P.R.), R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402 RFA-HL-09-004, American Cancer Society Research Scholar Grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, the Thoracic Foundation, the Ellison Foundation, the BCH-Broad Institute Award, The Harvard Medical School Translational Seed Grant and the Harvard Stem Cell Institute (C.F.K.), K22 CA201036 (C.F.B.), American Lung Association and ATS Foundation (H.W.), and the National Cancer Institute R01 CA195740, CA205150, CA166480, CA140594, CA216188, P01 CA154303, and U01 CA213333 (K.K.W.).
Data are available upon reasonable request. The ChIP-seq data and RNA-seq that support the findings of this study have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE100455 and GSE120073.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-07077-1.
Rowbotham, S. P.; Li, F; Dost, A. F. M.; Louie, S. M.; Marsh, B. P.; Pessina, P.; Anbarasu, C. R.; Brainson, Christine Fillmore; Tuminello, S. J.; Lieberman, A.; Ryeom, S.; Schlaeger, T. M.; Aronow, B. J.; Watanabe, H.; Wong, K. K.; and Kim, C. F., "H3K9 Methyltransferases and Demethylases Control Lung Tumor-Propagating Cells and Lung Cancer Progression" (2018). Toxicology and Cancer Biology Faculty Publications. 78.