Functional interaction of histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) promotes breast cancer progression

Cao, Chunyu; Vasilatos, Shauna N.; Bhargava, Rohit; Fine, Jeffrey L.; Oesterreich, Steffi; Davidson, Nancy E.; Huang, Yi

doi:10.1038/onc.2016.186

Cited by 85 publications

(92 citation statements)

References 45 publications

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“…By gain- and loss-of-function studies using a breast tumor progression model, we have observed that HDAC5 possesses a critical oncogenic function in driving MCF10A transformation via blocking LSD1 protein degradation and reshaping epigenetic landscape. 5 Our findings have revealed an important mechanism about the epigenetic regulation of LSD1 activity by HDAC5 that may lead to an alternative treatment approach against breast cancer.…”

Section: Introductionmentioning

confidence: 76%

“…We recently demonstrated that HDAC5 stabilizes LSD1 protein through down-regulation of LSD1 ubiquitination and degradation. 5 To decipher whether SFN destabilizes LSD1 protein by regulating its ubiquitination modification, protein ubiquitination assays were conducted and showed that exposure to SFN led to a profound increase of LSD1 polyubiquitination in MDA-MB-231 cells (Fig. 3d).…”

Section: Resultsmentioning

confidence: 99%

“…Quantitative real-time PCR was carried out using the StepOne real-time PCR system as previously described 5 . All the probes for TaqMan® Gene Expression Assays were predesigned and provided by Life Technologies.…”

Section: Methodsmentioning

confidence: 99%

“…The assay was performed as previously described 5 . Whole cell lysate was obtained using RIPA lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

“…We identified a unique feature of HDAC5 in facilitating protein stabilization of FAD-dependent histone demethylase 1 (LSD1), leading to a dysregulated chromatin landscape which functions as an antibraking system in breast cancer development. 5 Coordinated overexpression of HDAC5 and LSD1 proteins was observed in breast cancer cell lines and clinical patient samples. By gain- and loss-of-function studies using a breast tumor progression model, we have observed that HDAC5 possesses a critical oncogenic function in driving MCF10A transformation via blocking LSD1 protein degradation and reshaping epigenetic landscape.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The assay was performed as previously described 5 . Whole cell lysate was obtained using RIPA lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

2018

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Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well‐known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4‐TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene‐induced senescence). Unlike RAS, HDAC4‐induced OIS was TP53‐dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX‐positive foci. The inactivation of both TP53 and of the retinoblastoma (pRb) tumor suppressors, as induced by the viral oncogenes large and small T of SV40, triggers anchorage‐independent growth in RAS, HDAC4‐TM and, to a lesser extent, in HDAC4‐wild type (WT)‐expressing cells. Our results suggest an oncogenic function of class IIa HDACs in human cells, and justify further efforts to discover and evaluate isoform‐specific inhibitors of these epigenetic regulators from a therapeutic perspective.

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OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

Gong

Ding

et al. 2021

Advanced Science

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Genomic amplification of OTUD7B is frequently found across human cancers. But its role in tumorigenesis is poorly understood. Lysine‐specific demethylase 1 (LSD1) is known to execute epigenetic regulation by forming corepressor complex with CoREST/histone deacetylases (HDACs). However, the molecular mechanisms by which cells maintain LSD1/CoREST complex integrity are unknown. Here, it is reported that LSD1 protein undergoes K63‐linked polyubiquitination. OTUD7B is responsible for LSD1 deubiquitination at K226/277 residues, resulting in dynamic control of LSD1 binding partner specificity and cellular homeostasis. OTUD7B deficiency increases K63‐linked ubiquitination of LSD1, which disrupts LSD1/CoREST complex formation and targets LSD1 for p62‐mediated proteolysis. Consequently, OTUD7B deficiency impairs genome‐wide LSD1 occupancy and enhances the methylation of H3K4/H3K9, therefore profoundly impacting global gene expression and abrogating breast cancer metastasis. Moreover, physiological fluctuation of OTUD7B modulates cell cycle‐dependent LSD1 oscillation, ensuring the G1/S transition. Both OTUD7B and LSD1 proteins are overpresented in high‐grade or metastatic human breast cancer, while dysregulation of either protein is associated with poor survival and metastasis. Thus, OTUD7B plays a unique partner‐switching role in maintaining the integrity of LSD1/CoREST corepressor complex, LSD1 turnover, and breast cancer metastasis.

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Functional interaction of histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) promotes breast cancer progression

Cited by 85 publications

References 45 publications

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

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

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

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