H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression

Abstract

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.

Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression

“…Our work and that of others (Avgustinova et al 2018;Rowbotham et al 2018) warn that the treatment of cancers with inhibitors of H3K9-HMTs may augment genomic instability and thus, in the long run, favor more severe forms of cancer. On the other hand, for tumors that are deficient for BRCA1, treatment with G9a or other H3K9-HMT inhibitors may enhance cell death, like the synthetic lethality we score in worms.…”

“…The more than additive appearance of satellite transcripts and R loops in met-2 and brc-1 mutants, but not in the set-25 mutant, argues that the expression of simple repeats, and not transposons, renders cells highly dependent on the BRCA1/BARD1 complex. Since different HMTs target the classes of repeats independently, this has important implications for the treatment of tumors with H3K9-HMT inhibitors (Rowbotham et al 2018). Two recent studies have highlighted the fact that inhibitors of G9a, one of the HMTs responsible for H3K9me2 levels in mammalian cells, leads to genome instability and the delayed appearance of highly aggressive forms of skin and lung tumors (Avgustinova et al 2018;Rowbotham et al 2018).…”

“…Elevated levels of satellite transcripts are detected in brca1deficient tumors, as well as in normal mouse neuronal tissues depleted for BRCA1 (Zhu et al 2011(Zhu et al , 2018. Recent work confirms that G9a inhibition can generate more aggressive skin and lung tumors (Avgustinova et al 2018;Rowbotham et al 2018).…”

G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program

“…However, more recent studies have suggested that 449 the effects of epigenetic inhibitors can be more complex, and are likely to be context-dependent. For instance, 450 two recent studies have shown that inhibition of G9a drives the formation of tumors with more aggressive, 451 stem-like phenotypes Rowbotham et al, 2018). In the study by Avgustinova et al,452 G9a knock out delayed the formation of carcinogen-induced skin tumors, but once G9a-knockout tumors 453 formed they were more aggressive, with higher levels of genomic instability and more frequent p53 loss 454 .…”

Epigenetic Mechanisms in Canine Cancer

“…For example, some studies revealed a global loss of acetylated H4-lysine 16 (H4K16ac) and H4-lysine 20 trimethylation (H4K20me3) in different cancer cell lines and primary tumors, such as leukemia, breast, lung, and colon cancer (89). In addition, alterations of H3K9me and H3K27me patterns are also observed in different types of human cancer, including bladder, colorectal, glioma, breast, and lung cancer (90)(91)(92)(93)(94). Accordingly, the expression of enzymes responsible for these modifications, histone acetylases/ deacetylases (HATs and HDACs) and histone methyltransferases (HMTs), is observed to be dysregulated in cancer.…”