Expression of Hypoxia-Inducible Factor-1α, Histone Deacetylase 1, and Metastasis-Associated Protein 1 in Pancreatic Carcinoma

Miyake, Kotaro; Yoshizumi, Tomoharu; Imura, Satoru; Sugimoto, Koji; Batmunkh, Erdenebulgan; Kanemura, Hirofumi; Morine, Yuji; Shimada, Mitsuo

doi:10.1097/mpa.0b013e31815f2c2a

Cited by 153 publications

(53 citation statements)

References 38 publications

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“…Histone hypoacetylation or HDACs overexpression has been linked to the development of prostate, breast, ovarian, colon, and gastric cancer [19]. It has been shown that HDACs are overexpressed in PDAC [20] and that this, together with HIF-1a overexpression, is associated with worsening of survival prognosis [21]. …”

Section: Discussionmentioning

confidence: 99%

Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation

Relles

Chipitsyna

Gong

et al. 2016

Advances in Preventive Medicine

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Pancreatic ductal adenocarcinoma (PDAC) is virtually therapy-resistant. As noninvasive lesions progress to malignancy, the precursor period provides a window for cancer therapies that can interfere with neoplastic progression. Thymoquinone (Tq), a major bioactive component of essential oil from Nigella sativa's seeds, has demonstrated antineoplastic activities in multiple cancers. In this study, we investigated antineoplastic potential of Tq in human PDAC cell lines, AsPC-1 and MiaPaCa-2. Tq (10–50 μM) inhibited cell viability and proliferation and caused partial G2 cycle arrest in dose-dependent manner in both cell lines. Cells accumulated in subG0/G1 phase, indicating apoptosis. This was associated with upregulation of p53 and downregulation of Bcl-2. Independently of p53, Tq increased p21 mRNA expression 12-fold. Tq also induced H4 acetylation (lysine 12) and downregulated HDACs activity, reducing expression of HDACs 1, 2, and 3 by 40–60%. In vivo, Tq significantly reduced tumor size in 67% of established tumor xenografts (P < 0.05), along with increased H4 acetylation and reduced HDACs expression. Our results showed that Tq mediated posttranslational modification of histone acetylation, inhibited HDACs expression, and induced proapoptotic signaling pathways. These molecular targets demonstrate rationale for using Tq as a promising antineoplastic agent to prevent postoperative cancer recurrence and to prolong survival of PDAC patients after surgical resection.

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Section: Discussionmentioning

confidence: 99%

Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation

Relles

Chipitsyna

Gong

et al. 2016

Advances in Preventive Medicine

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show abstract

“…In another expression profile of class I HDACs, HDAC1, HDAC2, HDAC3 and HDAC8 were positive in 17 (85%), 18 (90%), 20 (100%) and 18 (90%) of 20 pancreatic cancer cases, respectively, as observed by immunohistochemistry [48]. Further studies in PDAC have linked elevated HDAC1 and HDAC2 levels with poor tumor differentiation and overall survival [49–51]. Ouaïssi, et al reported that approximately 80% of examined PDAC samples had a significant increase of HDAC7 at the RNA and protein levels [52].…”

Section: Nucleosome Remodeling Machines and Histone Modifying Enzymesmentioning

confidence: 99%

The Triple-Code Model for Pancreatic Cancer

Lomberk¹,

Urrutia²

2015

Surgical Clinics of North America

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Pancreatic adenocarcinoma (PDAC) is a lethal and painful disease, which has become one of the most frequent causes of death by malignant diseases around the world. Unfortunately, for the most part, this disease remains incurable. Significant advances in the field of genetics, particularly during the last two decades, has led to the proposal of a progression model, by which this cancer evolves by the accumulation of mutations and deletions in key oncogenes and tumor suppressor genes. This model has been remarkably useful for the development of tumor markers as well as elegant animal models. In spite of these strengths, this model does not take into consideration concepts and methodologies that have been derived from the field of epigenetics nor studies in the field of nuclear structure and function. Since our laboratory has been long been an advocate of these changes as critical for the pathobiology of pancreatic cancer, in this article, we describe an updated, more comprehensive model, which includes these concepts. With the widespread utilization of next generation sequencing for identifying both genetic and epigenetic changes genome-wide, we believe that the framework of this model will help to further identify and validate not only more but better markers for pancreatic cancer. In addition, as opposed to genetic changes, epigenetic alterations are amenable to pharmacological manipulations, consequently the familiarization with this model will help to better understand the potential beneficial effects of this type of therapy for this disease. Thus, we are optimistic that this new integrated paradigm will contribute to advance this field of research not only from a mechanistic point of view, but also from a translational one.

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“…The exact mechanisms by which these drugs act in cancer therapy is not fully understood, but they appear to have pleiotropic anti-tumor effects including induction of differentiation, growth arrest, initiation of senescence, enhanced apoptosis, decreased angiogenesis, immunomodulatory activities, and an ability to synergize with traditional cytotoxic chemotherapies and radiation [Deroanne et al, 2002; Kim et al, 2003; Bolden et al, 2006; Minucci and Pelicci, 2006; Tomasi et al, 2006; Xu et al, 2007]. The clinical utility of agents that target HDAC enzymes is, in part, based upon the aberrant expression and/or function of HDACs in cancer initiation and progression, with overexpression of some HDACs correlating with poor prognosis in a number of tumor types including gastric, prostate, breast, pancreatic, lung, and hepatocellular cancers [Rikimaru et al, 2007; Miyake et al, 2008; Weichert et al, 2008a b c]. …”

mentioning

confidence: 99%

A systems biology approach to identify molecular pathways altered by HDAC inhibition in osteosarcoma

Wittenburg

Ptitsyn

Thamm

2012

J of Cellular Biochemistry

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Osteosarcoma (OS) is the most common primary tumor in humans and dogs affecting the skeleton, and spontaneously occurring OS in dogs serves as an extremely useful model. Unacceptable toxicities using current treatment protocols prevent further dose-intensification from being a viable option to improve patient survival and thus, novel treatment strategies must be developed. Histone deacetylase inhibitors (HDACi) have recently emerged as a promising class of therapeutics demonstrating an ability to enhance the anti-tumor activity of traditional chemotherapeutics. To date, gene expression analysis of OS cell lines treated with HDACi has not been reported, and evaluation of the resultant gene expression changes may provide insight into the mechanisms that lead to success of HDACi. Canine OS cells, treated with a clinically relevant concentration of the HDACi valproic acid (VPA), were used for expression analysis on the Affymetrix canine v2.0 genechip. Differentially expressed genes were grouped into pathways based upon functional annotation; pathway analysis was performed with MetaCore and Ingenuity Pathways Analysis software. Validation of microarray results was performed by a combination of qRT-PCR and functional/biochemical assays revealing oxidative phosphorylation, cytoskeleton remodeling, cell cycle, and ubiquitin-proteasome among those pathways most affected by HDACi. The mitomycin C-bioactivating enzyme NQ01 also demonstrated upregulation following VPA treatment, leading to synergistic reductions in cell viability. These results provide a better understanding of the mechanisms by which HDACi exert their effect in OS, and have the potential to identify biomarkers that may serve as novel targets and/or predictors of response to HDACi-containing combination therapies in OS.

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Expression of Hypoxia-Inducible Factor-1α, Histone Deacetylase 1, and Metastasis-Associated Protein 1 in Pancreatic Carcinoma

Abstract: These results suggest that HIF-1alpha expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis for pancreatic carcinoma and indicates that HIF-1alpha and HDAC1/MTA1 are a promising therapeutic target in pancreatic carcinoma treatment.

Cited by 153 publications

References 38 publications

Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation

Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation

The Triple-Code Model for Pancreatic Cancer

A systems biology approach to identify molecular pathways altered by HDAC inhibition in osteosarcoma

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