Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib
Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with <i>BRCA1/2</i> mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib....
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/23/5580 |
| _version_ | 1797400383183650816 |
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| author | Siche Chen Heike Allgayer |
| author_facet | Siche Chen Heike Allgayer |
| author_sort | Siche Chen |
| collection | DOAJ |
| description | Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with <i>BRCA1/2</i> mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of the <i>BRCA2</i> gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain of <i>BRCA2</i> may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors. |
| first_indexed | 2024-03-09T01:53:50Z |
| format | Article |
| id | doaj.art-67761183426f4872bf8dc962f4f7f3b6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T01:53:50Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-67761183426f4872bf8dc962f4f7f3b62023-12-08T15:12:36ZengMDPI AGCancers2072-66942023-11-011523558010.3390/cancers15235580Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to OlaparibSiche Chen0Heike Allgayer1Department of Experimental Surgery—Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, GermanyDepartment of Experimental Surgery—Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, GermanyOlaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with <i>BRCA1/2</i> mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of the <i>BRCA2</i> gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain of <i>BRCA2</i> may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.https://www.mdpi.com/2072-6694/15/23/5580olaparib sensitivityBRCA2KAT2Bcolorectal cancerH3K27acγH2AX |
| spellingShingle | Siche Chen Heike Allgayer Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib Cancers olaparib sensitivity BRCA2 KAT2B colorectal cancer H3K27ac γH2AX |
| title | Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib |
| title_full | Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib |
| title_fullStr | Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib |
| title_full_unstemmed | Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib |
| title_short | Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib |
| title_sort | epigenetically downregulated breast cancer gene 2 through acetyltransferase lysine acetyltransferase 2b increases the sensitivity of colorectal cancer to olaparib |
| topic | olaparib sensitivity BRCA2 KAT2B colorectal cancer H3K27ac γH2AX |
| url | https://www.mdpi.com/2072-6694/15/23/5580 |
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