Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells
Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/12/2/260 |
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| author | Michèle J. Hoffmann Sarah Meneceur Katrin Hommel Wolfgang A. Schulz Günter Niegisch |
| author_facet | Michèle J. Hoffmann Sarah Meneceur Katrin Hommel Wolfgang A. Schulz Günter Niegisch |
| author_sort | Michèle J. Hoffmann |
| collection | DOAJ |
| description | Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted. |
| first_indexed | 2024-03-09T04:43:35Z |
| format | Article |
| id | doaj.art-0e88d1d412df4f4584606b9191a765e2 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T04:43:35Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-0e88d1d412df4f4584606b9191a765e22023-12-03T13:17:24ZengMDPI AGGenes2073-44252021-02-0112226010.3390/genes12020260Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer CellsMichèle J. Hoffmann0Sarah Meneceur1Katrin Hommel2Wolfgang A. Schulz3Günter Niegisch4Department of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanySince genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted.https://www.mdpi.com/2073-4425/12/2/260bladder cancercell cycle genecell cycle arrestHDACepigenetic inhibitorRomidepsin |
| spellingShingle | Michèle J. Hoffmann Sarah Meneceur Katrin Hommel Wolfgang A. Schulz Günter Niegisch Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells Genes bladder cancer cell cycle gene cell cycle arrest HDAC epigenetic inhibitor Romidepsin |
| title | Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells |
| title_full | Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells |
| title_fullStr | Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells |
| title_full_unstemmed | Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells |
| title_short | Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells |
| title_sort | downregulation of cell cycle and checkpoint genes by class i hdac inhibitors limits synergism with g2 m checkpoint inhibitor mk 1775 in bladder cancer cells |
| topic | bladder cancer cell cycle gene cell cycle arrest HDAC epigenetic inhibitor Romidepsin |
| url | https://www.mdpi.com/2073-4425/12/2/260 |
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