HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability

Krishnan, Moorthy; Singh, Amar B.; Smith, J. Joshua; Sharma, Ashok; Chen, X; Eschrich, Steven; Yeatman, Tim; Beauchamp, R. Daniel; Dhawan, Punita

doi:10.1038/onc.2009.324

Cited by 86 publications

(82 citation statements)

References 20 publications

(29 reference statements)

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“…Cdx2 can cooperate with Wnt pathway to regulate CLDN1 expression in colon cancer cells (29). The CLDN1 mRNA stability can also be regulated HDACdependently (31,32). To our knowledge, the immuno-profiles of CLDN1 and its association with β-catenin have not previously been reported in gastric cancer.…”

Section: Introductionmentioning

confidence: 91%

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Huang

et al. 2014

International Journal of Oncology

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Abstract. Claudin 1 is one of the tight junction proteins, which are critical in the maintenance of epithelial integrity. Aberrant regulation of CLDN1 and its correlation with β-catenin have been discovered in malignant tumors. The present study aimed to investigate the expression profile and clinical relevance of CLDN1 and β-catenin. The protein levels of CLDN1 and β-catenin were examined using immunohistochemical staining. The characteristics of expression profile and prognostic value were analyzed using Pearson's χ 2 test and Kaplan-Meier analysis, respectively. β-catenin overexpression and knockdown were used to investigate its role in regulating CLDN1 expression. We showed that CLDN1 was overexpressed in intestinal-type, presence of lymph node metastasis, higher TNM stage in gastric cancer patients and correlated with decreased overall survival. The characteristics of CLDN1 expression were associated with that of β-catenin. CLDN1 and β-catenin showed similar prognostic value in intestinal-type gastric cancers. β-catenin knockdown and overexpression in cell models revealed a positive relation between CLDN1 and β-catenin. Our study demonstrated that CLDN1 is a biomarker for intestinal-type gastric cancer with shorter survival. The expression of CLDN1 was strongly associated with β-catenin in gastric cancer patients and a gastric cancer cell model. IntroductionGastric cancer is the fourth most common cancer worldwide and is the second most common cause of cancer-related deaths.Gastric cancer has a poor prognosis (1). Although the 5-year survival rate in patients with early-stage disease is ~90%, since the vast majority present with distant metastasis, the overall 5-year survival rate is typically <20% (2). The 5-year survival rate has also been significantly correlated with the degree of tumor invasion, the presence of lymph node and/ or distant metastases and the TNM stage (3,4). However, very limited number of molecules that have clinicopathological significance in gastric cancer has been discovered.Claudin 1 (CLDN1) is one of the integral membrane proteins that constitute tight junctions. Tight junctions are essential for the tight sealing of cellular sheets and maintaining homeostasis (5). Absence of tight junctions or defective tight junctions is associated with the development of the neoplastic phenotype in epithelial cells (6). Thus it is accepted that the disruption of tight junctions leads to loss of cohesion, invasiveness and the lack of differentiation, thereby promoting tumorigenesis. CLDN1 is found to regulate intestinal epithelial homeostasis through the modulation of Notch-signaling (7). Many chemicals and nutrition can regulate CLDN1 expression through different pathways (8,9) to maintain the integrity of intestinal barrier function.The complexity of CLDN1 was proposed because its dual role as a tumor suppressor and promoter, as well as a positive and negative prognostic factor in different cancers, including breast (10,11), gastric (12), ovarian (13), lung (14) and colon (15-17). Decreased exp...

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Section: Introductionmentioning

confidence: 91%

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Huang

et al. 2014

International Journal of Oncology

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“…In addition to transcriptional regulation, HDACi have been reported to affect mRNA stability. 43,44 However, SAHA treatment did not further reduce B7-H6 mRNA levels when de novo transcription was blocked by actinomycin D, indicating that SAHA does not affect B7-H6 mRNA stability ( Figure 4E). Together, these data show that HDACi treatment reduces B7-H6 reporter activity as well as the binding of HDAC3 and the HAT CBP to the B7-H6 59-UTR and leads to local histone hypoacetylation.…”

Section: B7-h6 Expression Is Reduced By Inhibitors Of Class I Hdacs Amentioning

confidence: 99%

Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells

Fiegler

Textor

Arnold

et al. 2013

Blood

110

107

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“…High levels of HDAC2 have been found in colorectal, cervical and gastric cancers 11,12 . In addition, HDAC3 is overexpressed in gastric, prostate and colorectal cancer 13 , and high expression of HDAC1 and 2 correlates with reduced patient survival in colorectal carcinomas 14,15 . HDAC6 is highly expressed in breast cancer, HDAC8 is over-expressed in neuroblastoma cells and its overexpression correlates with metastasis and advanced stage of disease with poor prognosis.…”

Section: Histone Deacetylases and Cancermentioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

BIOMED PAP

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability

Cited by 86 publications

References 20 publications

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells

Histone deacetylase inhibitors in cancer therapy. A review

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