HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells

Hsieh, Tsung Hua; Hsu, Chia‐Yi; Tsai, Cheng Fang; Long, Cheng‐Yu; Wu, Chin Hu; Wu, Deng Chyang; Lee, Jau Nan; Chang, Wei Chun; Tsai, Eing Mei

doi:10.1038/mt.2014.247

Cited by 89 publications

(76 citation statements)

References 44 publications

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“…The present study shows that HDAC5 mRNA and protein were both widely expressed in breast tumor tissues and that the relatively high expression of HDAC5 was associated with an inferior prognosis in patients with BC. In addition, functional studies confirmed the oncogenic effects of HDAC5 in BC, which are consistent with the findings of Hsieh et al [10]. …”

Section: Discussionsupporting

confidence: 91%

“…Moreover, Peixoto et al demonstrated that HDAC5 maintains pericentric heterochromatin structures in human cancer cells and thus represents a potential anticancer drug target [9]. Subsequently, Hsieh et al reported that pan-HDAC inhibitors (pan-HDACis) induce BC apoptosis via the upregulation of microRNA (miR)-125a-5p, which post-transcriptionally silences HDAC5 [10]. …”

Section: Introductionmentioning

confidence: 99%

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HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Liu

et al. 2016

Oncotarget

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PurposeHistone deacetylase 5 (HDAC5) is an important protein in neural and cardiac diseases and a potential drug target. However, little is known regarding the specific role of HDAC5 in breast cancer (BC). We aimed to evaluate HDAC5 expression in human breast tumors and to determine the effects of the inhibition of HDAC5 expression in BC cells.Experimental designHDAC5 expression was evaluated in BC patients and was correlated with clinical features and with patient prognosis. Functional experiments were performed using shRNA and the selective HDAC inhibitor LMK-235 for HDAC5 knockdown and inhibition in BC cells. The synergistic effects of LMK-235 with the proteasome inhibitor bortezomib were also examined.ResultsHDAC5 was extensively expressed in human BC tissues, and high HDAC5 expression was associated with an inferior prognosis. Knockdown of HDAC5 inhibited cell proliferation, migration, invasion, and enhanced apoptosis. The HDAC5 inhibitor LMK-235 inhibited cell growth and induced apoptosis, while the inclusion of bortezomib synergistically enhanced the efficacy of LMK-235.ConclusionsOur findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Liu

et al. 2016

Oncotarget

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“…It has been demonstrated that the epigenetic modulators could modulate the miR‐125‐5p expression,13, 25, 26 and its promoter is hypermethylated in glioma cells 27. We analysed the miR‐125a‐5p methylation status in gastric cancer tissues and adjacent non‐tumour tissues.…”

Section: Resultsmentioning

confidence: 99%

Retracted: Epigenetic silenced miR‐125a‐5p could be self‐activated through targeting Suv39H1 in gastric cancer

Cai

Chen

Shen

et al. 2018

J Cellular Molecular Medi

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Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumorigenesis and development. Although the low expression of miR‐125a‐5p in gastric cancer has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR‐125a‐5p in gastric cancer was verified in paired cancer tissues and adjacent non‐tumour tissues. Furthermore, the GC islands in the miR‐125a‐5p region were hypermethylated in the tumour tissues. And the hypermethylation was negatively correlated with the miR‐125a‐5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR‐125a‐5p could directly suppress the Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, the Suv39H1 could induce demethylation of miR‐125a‐5p, resulting in re‐activation of miR‐125a‐5p. What is more, overexpessing miR‐125a‐5p could also self‐activate the silenced miR‐125a‐5p in gastric cancer cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo. Thus, we uncovered here that the epigenetic silenced miR‐125a‐5p could be self‐activated through targeting Suv39H1 in gastric cancer, suggesting that miR‐125a‐5p might be not only the potential prognostic value as a tumour biomarker but also potential therapeutic targets in gastric cancer.

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“…HDAC5 is a key class II HDAC isozyme that has been shown to possess critical roles in many diseases including cancers. 8, 9, 34, 35 Our recent tissue microarray study found that breast tumors expressed overall higher levels of HDAC5 protein compared to the matched adjacent normal tissues. 5 Importantly, our analysis showed that elevated HDAC5 protein expression is positively correlated with higher stages of clinical breast cancer.…”

Section: Discussionmentioning

confidence: 99%

HDAC5–LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells

Cao

Vasilatos

et al. 2018

Intl Journal of Cancer

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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.

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HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells

Cited by 89 publications

References 44 publications

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Retracted: Epigenetic silenced miR‐125a‐5p could be self‐activated through targeting Suv39H1 in gastric cancer

HDAC5–LSD1 axis regulates antineoplastic effect of natural HDAC inhibitor sulforaphane in human breast cancer cells

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