Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a...
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2019-12-01
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Series: | Molecular Therapy: Oncolytics |
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doaj-710da8fe56c04d2f8fa3bd09c61234b32020-11-25T00:26:41ZengElsevierMolecular Therapy: Oncolytics2372-77052019-12-0115140152Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast CancerWoong Sub Byun0Won Kyung Kim1Hae Ju Han2Hwa-Jin Chung3Kyungkuk Jang4Han Sun Kim5Sunghwa Kim6Donghwa Kim7Eun Seo Bae8Sunghyouk Park9Jeeyeon Lee10Hyeung-geun Park11Sang Kook Lee12College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of KoreaCollege of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea; Corresponding author: Sang Kook Lee, College of Pharmacy, Natural Products Research Institute, Seoul National University, 1 Gwanak-gu, Gwanak-ro, Seoul 08826, Republic of Korea.Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients. Keywords: histone methyltransferase DOT1L, H3K79 methylation, psammaplin A analog (PsA-3091), triple-negative breast cancer, metastasis, epithelial-mesenchymal transition (EMT)http://www.sciencedirect.com/science/article/pii/S2372770519300890 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Woong Sub Byun Won Kyung Kim Hae Ju Han Hwa-Jin Chung Kyungkuk Jang Han Sun Kim Sunghwa Kim Donghwa Kim Eun Seo Bae Sunghyouk Park Jeeyeon Lee Hyeung-geun Park Sang Kook Lee |
spellingShingle |
Woong Sub Byun Won Kyung Kim Hae Ju Han Hwa-Jin Chung Kyungkuk Jang Han Sun Kim Sunghwa Kim Donghwa Kim Eun Seo Bae Sunghyouk Park Jeeyeon Lee Hyeung-geun Park Sang Kook Lee Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer Molecular Therapy: Oncolytics |
author_facet |
Woong Sub Byun Won Kyung Kim Hae Ju Han Hwa-Jin Chung Kyungkuk Jang Han Sun Kim Sunghwa Kim Donghwa Kim Eun Seo Bae Sunghyouk Park Jeeyeon Lee Hyeung-geun Park Sang Kook Lee |
author_sort |
Woong Sub Byun |
title |
Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer |
title_short |
Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer |
title_full |
Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer |
title_fullStr |
Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer |
title_full_unstemmed |
Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer |
title_sort |
targeting histone methyltransferase dot1l by a novel psammaplin a analog inhibits growth and metastasis of triple-negative breast cancer |
publisher |
Elsevier |
series |
Molecular Therapy: Oncolytics |
issn |
2372-7705 |
publishDate |
2019-12-01 |
description |
Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients. Keywords: histone methyltransferase DOT1L, H3K79 methylation, psammaplin A analog (PsA-3091), triple-negative breast cancer, metastasis, epithelial-mesenchymal transition (EMT) |
url |
http://www.sciencedirect.com/science/article/pii/S2372770519300890 |
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