Abstract
Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at −356 to −100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5–LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5–LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.
Original language | English (US) |
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Pages (from-to) | 1388-1401 |
Number of pages | 14 |
Journal | International Journal of Cancer |
Volume | 143 |
Issue number | 6 |
DOIs | |
State | Published - Sep 15 2018 |
Funding
Key words: breast cancer, HDAC5, LSD1, USF1, sulforaphane, HCI-2509, combination therapy Additional Supporting Information may be found in the online version of this article. §C.C. and H.W. contributed equally to this work Conflicts of interest: The authors declare no conflict of interest. Grant sponsor: US Army Breast Cancer Research Programs; Grant numbers: W81XWH-14–1-0237, W81XWH-14–1-0238; Grant sponsor: Breast Cancer Research Foundation; Grant sponsor: NIH; Grant number: P30CA047904; Grant sponsor: China Scholarship Council and Project of Science and Technology Department of Qinghai Province of China; Grant number: 2015-ZJ-751 DOI: 10.1002/ijc.31419 History: Received 21 Dec 2017; Accepted 28 Mar 2018; Online 6 Apr 2018 Correspondence to: Yi Huang, M.D., Ph.D., Magee Womens Research Institute, Room 406, 204 Craft Ave, Pittsburgh, PA 15213, USA, Tel.: 11-412-641-3589; E-mail: [email protected]
Keywords
- HCI-2509
- HDAC5
- LSD1
- USF1
- breast cancer
- combination therapy
- sulforaphane
ASJC Scopus subject areas
- Oncology
- Cancer Research