Lovastatin Suppresses the Transcriptional Regulation of &lt;i&gt;CLDND1&lt;/i&gt; in Human Hepatoma Cells

Shima, Akiho; Matsuoka, Hiroshi; MIYA, Kaoruko; Michihara, Akihiro

doi:10.1248/bpbreports.3.4_113

Cited by 4 publications

(1 citation statement)

References 29 publications

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“…In addition, CLDND1 is expressed in the liver, testes, and brain, with the expression distribution strongly correlating with retinoic acid receptor-related orphan receptor α (RORα), which is involved in the transcriptional regulation of CLDND1 [ 18 , 19 ]. RORα relies on cholesterol as a ligand to regulate transcription [ 20 , 21 ], and inhibition of cholesterol synthesis by statin treatment has been shown to reduce the transcriptional regulation of CLDND1 by RORα [ 22 ]. The post-transcriptional regulation of CLDND1 is regulated by microRNA-124 [ 23 ].…”

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confidence: 99%

EGF-Dependent Activation of ELK1 Contributes to the Induction of CLDND1 Expression Involved in Tight Junction Formation

et al. 2022

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Claudin proteins are intercellular adhesion molecules. Increased claudin domain-containing 1 (CLDND1) expression is associated with the malignant transformation of estrogen receptor-negative breast cancer cells with low sensitivity to hormone therapy. Abnormal CLDND1 expression is also implicated in vascular diseases. Previously, we investigated the regulatory mechanism underlying CLDND1 expression and identified a strong enhancer region near the promoter. In silico analysis of the sequence showed high homology to the ETS domain-containing protein-1 (ELK1)-binding sequence which is involved in cell growth, differentiation, angiogenesis, and cancer. Transcriptional ELK1 activation is associated with the mitogen-activated protein kinase (MAPK) signaling cascade originating from the epidermal growth factor receptor (EGFR). Here, we evaluated the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on the suppression of CLDND1 expression using ELK1 overexpression in luciferase reporter and chromatin immunoprecipitation assays. ELK1 was found to be an activator of the enhancer region, and its transient expression increased that of CLDND1 at the mRNA and protein levels. CLDND1 expression was increased following EGF-induced ELK1 phosphorylation. Furthermore, this increase in CLDND1 was significantly suppressed by gefitinib. Therefore, EGF-dependent activation of ELK1 contributes to the induction of CLDND1 expression. These findings open avenues for the development of new anticancer agents targeting CLDND1.

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Section: Introductionmentioning

confidence: 99%

EGF-Dependent Activation of ELK1 Contributes to the Induction of CLDND1 Expression Involved in Tight Junction Formation

et al. 2022

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Identification of the RORα Transcriptional Network Contributes to the Search for Therapeutic Targets in Atherosclerosis

Matsuoka

Michihara

2021

Biological & Pharmaceutical Bulletin

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Transcription of CLDND1 is Regulated Mainly by the Competitive Action of MZF1 and SP1 that Binds to the Enhancer of the Promoter Region

et al. 2020

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Increased permeability of vascular endothelial cells in the brain is an underlying cause of stroke, which is associated with high mortality rates worldwide. Vascular permeability is regulated by tight junctions (TJs) formed by claudin family and occludin proteins. In particular, increased vascular permeability is associated with decreased claudin domain-containing 1 (CLDND1) expression, which belongs to the TJs family. We previously reported that myeloid zinc finger 1 (MZF1) acts as an activator of CLDND1 expression by binding to its first intron. Several transcription factors regulate transcription by acting on the promoter regions of target genes. However, transcription factors acting on the promoter of CLDND1 are not completely elucidated. Thus, we focused on the promoter region of human CLDND1 to identify factors that could regulate its transcription. Reporter analysis of CLDND1 promoter region revealed an enhancer in the-742/-734 region with MZF1 and specificity protein 1 (SP1) binding sites. Chromatin immunoprecipitation assays confirmed that both MZF1 and SP1 could bind to CLDND1 enhancer region. MZF1 overexpression significantly increased CLDND1 expression, whereas overexpression of SP1 had no effect. Moreover, the identified enhancer region exhibited stronger transcriptional and binding capacity than the first intron. Thus, CLDND1 expression is more strongly regulated by competitive action of MZF1 and SP1 binding to the promoter-enhancer region than the first intron silencer region. These results provide novel insights for the development of potential therapies and preventive strategies for stroke in the future.

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Lovastatin Suppresses the Transcriptional Regulation of <i>CLDND1</i> in Human Hepatoma Cells

Cited by 4 publications

References 29 publications

EGF-Dependent Activation of ELK1 Contributes to the Induction of CLDND1 Expression Involved in Tight Junction Formation

EGF-Dependent Activation of ELK1 Contributes to the Induction of CLDND1 Expression Involved in Tight Junction Formation

Identification of the RORα Transcriptional Network Contributes to the Search for Therapeutic Targets in Atherosclerosis

Transcription of CLDND1 is Regulated Mainly by the Competitive Action of MZF1 and SP1 that Binds to the Enhancer of the Promoter Region

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