Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression

Song, Chenlin; Zhu, Shifeng; Wu, Chuanyue; Kang, Jiuhong

doi:10.1074/jbc.m113.498758

Cited by 113 publications

(83 citation statements)

References 38 publications

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“…10 Only recently, it has been reported to influence neuroblastoma cell survival by promoting autophagy, 45 but to suppress cervical cancer metastasis. 46 In contrast, increased HDAC10 expression in chronic lymphocytic leukemia patients was associated with poor prognosis. 47 In bladder cancer, no investigations on HDAC10 have been published to date.…”

Section: Discussionmentioning

confidence: 99%

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Rosik

Niegisch

Fischer

et al. 2014

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Rosik

Niegisch

Fischer

et al. 2014

Cancer Biology & Therapy

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“…ECM remodeling is an essential process during cancer invasion, angiogenesis, and metastasis. MMPs are a family of zincdependent endopeptidases that degrade all ECM components and play a key role in these processes (34,35). The expression of MMPs is highly regulated at many levels.…”

Section: Sicmentioning

confidence: 99%

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

Boufraqech

Zhang

Nilubol

et al. 2016

Clinical Cancer Research

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Purpose: Epithelial-to-mesenchymal transition (EMT) is important in cancer progression and metastasis. We and others have previously reported that lysyl oxidase (LOX) is overexpressed in aggressive cancers, is associated with increased mortality, and regulates EMT. However, the mechanism by which LOX mediates EMT is unknown. In this study, we investigated the effect of LOX on mediators of EMT.Experimental Design: We used chromatin immunoprecipitation and promoter luciferase assays to determine the target gene of LOX. To determine the effects of SNAI2 in vivo, we used our metastatic anaplastic thyroid cancer (ATC) mouse model. To investigate the effects of LOX and SNAI2 on MMPs and TIMPs, protein arrays were used. Primary tumors from patients with metastatic, breast and colon cancer, and tissue array for thyroid cancer were assessed for SNAI2 and TIMP4 expression by immunohistochemistry.Results: We found that LOX knockdown decreases SNAI2 expression in cancer cell lines. Furthermore, knockdown of LOX reduced SNAI2 expression in a metastatic mouse model of thyroid cancer. We also demonstrated that LOX binds and transactivates the SNAI2 promoter. We found a direct correlation in thyroid and breast cancer samples between LOX and SNAI2 expression. To understand how LOX/SNAI2 axis mediates these effects, we performed a comprehensive analysis of MMPs/TIMPs. LOX and SNAI2 depletion reduced TIMP4 secretion. Analysis of SNAI2 and TIMP4 expression showed overexpression of both proteins in aggressive thyroid, colon, and breast tumors.Conclusions: Our findings provide new evidence that LOX regulates SNAI2 expression and that SNAI2-mediated TIMP4 secretion plays a role in cancer progression.

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“…HDAC10 is involved in transcriptional downregulation of TXNIP, leading to altered signaling in response to reactive oxygen species and apoptosis in human gastric cancer cells (25). HDAC10 binds to the MMP2 and -9 promoters, reduces histone acetylation, and inhibits transcription in cervical cancer cells (26). In addition to transcriptional regulation, HDAC10 might also target nonhistone proteins.…”

mentioning

confidence: 99%

Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

Peng

Seto

2015

Molecular and Cellular Biology

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Histone deacetylase (HDAC) inhibition leads to cell cycle arrest in G 1 and G 2 , suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G 2 /M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation. Histone function is modulated by several posttranslational modifications, including reversible acetylation of the N-terminal ε-group of lysines on histones (1). Histone acetylation is tightly controlled by a balance between the opposing activities of histone acetyltransferases and histone deacetylases (HDACs). Acetylation of histone core molecules modulates chromatin structure and gene expression (2). The human HDAC family includes 18 members grouped into four classes. Class I HDACs, orthologs of Saccharomyces cerevisiae RPD3, are comprised of HDAC1, -2, -3, and -8. Class II, similar to yeast HDA1, has two subclasses: IIa (HDAC4, -5, -6, -7, and -9) and IIb (HDAC6 and -10). Class III, related to yeast SIR2, consists of seven sirtuins, which require NAD ϩ for activity. Class IV contains only HDAC11, which shows limited homologies to class I and II enzymes. Whereas class III HDACs are inhibited by nicotinamide, class I and II HDACs are dependent on Zn 2ϩ for deacetylase activity. The class IIb HDAC6 and HDAC10 are specifically sensitive to hydroxamate-type inhibitors (3), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Most hydroxamate inhibitors are nonselective, with the exception of tubacin and tabastatin A, which are selective for HDAC6 (4, 5). Another hydroxamate compound, bufexamac, also has been identified as a novel class IIb inhibitor that specifically inhibits HDAC6 at lower doses (3, 6). In addition, the cellular acetylome regulated by HDAC6 correlated with the profile observed after bufexamac treatment (6). However, the effect and mechanism of bufexamac on HDAC10 have not yet been well-studied. Thus, identification of the catalytic structure and mechanism of action of HDAC10 might inform the development of a selective inhibitor in future research.HDACs play important roles in the regulation of the cell cycle, apoptosis, stress responses, and DNA repair, indicating that they are key regulators of normal ...

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Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression

Cited by 113 publications

References 38 publications

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

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Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression

Cited by 113 publications

References 38 publications

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

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Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway