ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat
ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motili...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | European Journal of Cell Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933523000560 |
| _version_ | 1827813687665098752 |
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| author | Yang Yang Biao Ma Mahbod Djamshidi Qingrun Zhang Anusi Sarkar Ayan Chanda Uyen Tran Jung Soh Christina Sandall Huey-Miin Chen Justin A. MacDonald Shirin Bonni Christoph W. Sensen Jianhua Zheng Karl Riabowol |
| author_facet | Yang Yang Biao Ma Mahbod Djamshidi Qingrun Zhang Anusi Sarkar Ayan Chanda Uyen Tran Jung Soh Christina Sandall Huey-Miin Chen Justin A. MacDonald Shirin Bonni Christoph W. Sensen Jianhua Zheng Karl Riabowol |
| author_sort | Yang Yang |
| collection | DOAJ |
| description | ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-β-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation. |
| first_indexed | 2024-03-11T23:35:40Z |
| format | Article |
| id | doaj.art-1436a51a89e047f3b13b738b31e903d7 |
| institution | Directory Open Access Journal |
| issn | 0171-9335 |
| language | English |
| last_indexed | 2024-03-11T23:35:40Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Cell Biology |
| spelling | doaj.art-1436a51a89e047f3b13b738b31e903d72023-09-20T04:20:39ZengElsevierEuropean Journal of Cell Biology0171-93352023-09-011023151341ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostatYang Yang0Biao Ma1Mahbod Djamshidi2Qingrun Zhang3Anusi Sarkar4Ayan Chanda5Uyen Tran6Jung Soh7Christina Sandall8Huey-Miin Chen9Justin A. MacDonald10Shirin Bonni11Christoph W. Sensen12Jianhua Zheng13Karl Riabowol14Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR ChinaDepartment of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR ChinaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaLibin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, CanadaLibin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, CanadaLibin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, CanadaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, CanadaHCEMM Kft., Budapesti ut 9, 6728 Szeged, HungaryDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR ChinaArnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada; Correspondence to: 374 HMRB, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada.ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-β-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation.http://www.sciencedirect.com/science/article/pii/S0171933523000560Breast cancerEpigeneticsING1VorinostatEMTTwist1 |
| spellingShingle | Yang Yang Biao Ma Mahbod Djamshidi Qingrun Zhang Anusi Sarkar Ayan Chanda Uyen Tran Jung Soh Christina Sandall Huey-Miin Chen Justin A. MacDonald Shirin Bonni Christoph W. Sensen Jianhua Zheng Karl Riabowol ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat European Journal of Cell Biology Breast cancer Epigenetics ING1 Vorinostat EMT Twist1 |
| title | ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat |
| title_full | ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat |
| title_fullStr | ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat |
| title_full_unstemmed | ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat |
| title_short | ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat |
| title_sort | ing1 inhibits twist1 expression to block emt and is antagonized by the hdac inhibitor vorinostat |
| topic | Breast cancer Epigenetics ING1 Vorinostat EMT Twist1 |
| url | http://www.sciencedirect.com/science/article/pii/S0171933523000560 |
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