Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors

Abstract

Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Cotargeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle

Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition

“…For example, HDACi treatment thermally destabilizes the transcription factor MGA and the EHMT1/2 histone methyltransferase (Figure 7C). Both proteins are known to act downstream of HDAC1/2 and PRC1 (Chittock et al, 2017) as repressors of E2F- and Myc-responsive genes (Ogawa et al, 2002), and HDACi and EHMT1/2 inhibitors can synergistically improve antineoplastic activity compared to using HDACi alone (Bamberg et al, 2022). Interestingly, we observed no significant effect on the abundance of either MGA or EHMT1 in living cells after belinostat treatment (Figure 8D).…”

Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells

“…Inhibition of the euchromatic histone lysine methyltransferases 1 and 2 (EHMT1/2) enhanced the antiproliferative activity of HDAC inhibitors in colorectal cancer and reduced H3K9 methylation. 28 EZH2 is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyses the trimethylation of H3K27. Gain‐of‐function mutation in the catalytic SET domain of EZH2 was detected in lymphoma and increased H3K27me3.…”

“…HKMT inhibitors demonstrated antitumor effects in different types of cancer. Inhibition of the euchromatic histone lysine methyltransferases 1 and 2 (EHMT1/2) enhanced the antiproliferative activity of HDAC inhibitors in colorectal cancer and reduced H3K9 methylation 28 . EZH2 is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyses the trimethylation of H3K27.…”

An organoid platform reveals MEK-PARP co-targeting to enhance radiation response in rectal cancer

“…Sample sizes were chosen on the basis of experience with the given experiments. 14,62,63 Two-tailed unpaired Student’s t-test or Welch’s t-test were used to analyze statistical significance between two groups. Statistical analyses were performed using R v 4.4.0 or GraphPad Prism v 8.0.…”