Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer

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

doi:10.1016/j.omto.2019.09.005

Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer

Mol Ther Oncolytics. 2019 Oct 1:15:140-152. doi: 10.1016/j.omto.2019.09.005. eCollection 2019 Dec 20.

Authors

Affiliations

¹ College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
² College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.

Abstract

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: H3K79 methylation; epithelial-mesenchymal transition (EMT); histone methyltransferase DOT1L; metastasis; psammaplin A analog (PsA-3091); triple-negative breast cancer.