Academic Journal
Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors
| العنوان: | Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors |
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| المؤلفون: | Bamberg, Leonhard Valentin, Heigwer, Florian, Wandmacher, Anna Maxi, Singh, Ambika, Betge, Johannes, Rindtorff, Niklas, Werner, Johannes, Josten, Julia, Skabkina, Olga Valerievna, Hinsenkamp, Isabel, Erdmann, Gerrit, Röcken, Christoph, Ebert, Matthias P, Burgermeister, Elke, Zhan, Tianzuo, Boutros, Michael |
| المساهمون: | German Research Foundation, Ministerium für Wirtschaft, Arbeit und Wohnungsbau Baden-Württemberg |
| المصدر: | International Journal of Cancer ; volume 151, issue 9, page 1586-1601 ; ISSN 0020-7136 1097-0215 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2022 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | 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 arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient‐derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/ijc.34155 |
| الاتاحة: | http://dx.doi.org/10.1002/ijc.34155 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.34155 https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ijc.34155 |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| رقم الانضمام: | edsbas.1DB730A5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/ijc.34155 |
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