&lt;b&gt;Basic helix-loop-helix transcription factor DEC1 regulates the cisplatin-induced apoptotic pathway of human esophageal cancer &lt;/b&gt;&lt;b&gt;cells &lt;/b&gt;

Seino, Hiroko; Wu, Yunyan; Morohashi, Satoko; Kawamoto, Takeshi; Fujimoto, Katsumi; Kato, Yukio; Takai, Yoshihiro; Kijima, Hiroshi

doi:10.2220/biomedres.36.89

Cited by 16 publications

(14 citation statements)

References 23 publications

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“…E-box is ubiquitously expressed in the promoter of target genes, including E-cadherin, occludins, and claudins (Ikenouchi et al 2003 ). DEC1 directly regulate the target genes involved in many cancer cells (Bi et al 2015 ; Seino et al 2015 ). There are some similarities between carcinoma and IPF, so we examined whether DEC1 is involved in pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibition attenuates bleomycin-induced pulmonary fibrosis via switching the development of epithelial-mesenchymal transition

Liu

Zhang

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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Calpains are intracellular calcium-dependent cysteine proteases, which cleave several substrates proteins, have been proven to play important roles in lung fibrosis. The aim of this study was to investigate the effects of calpain on bleomycin (BLM)-induced pulmonary fibrosis. A lung fibrosis mice model was established successfully by intraperitoneal injection of bleomycin. Calpeptin, a highly selective inhibitor of calpain activation, was administered three times weekly after bleomycin injection. Histological examination was used to assess the fibrosis. Quantitative-PCR and Western blotting were used to assess the development of epithelial-mesenchymal transition (EMT). We found calpeptin treatment decreased the BLM-induced EMT-associated markers, such as muscle actin (α-SMA) and collagen-I, while increased E-cadherin (E-cad). Calpeptin also suppressed the activation of transforming growth factor β1 (TGFβ1)-Smad2/3 signaling pathway, which plays crucial role in lung fibrosis and EMT. Furthermore, we found differentiated embryonic chondrocyte-expressed gene 1 (DEC1), an important transcription factor, was upregulated in both patients with idiopathic pulmonary fibrosis and in bleomycin-induced lung fibrosis. DEC1 was suppressed by calpeptin in bleomycin-induced mice model. Collectively, these findings indicated that calpeptin had a potential anti-fibrosis effect, which focus on the development of EMT.Electronic supplementary materialThe online version of this article (10.1007/s00210-018-1499-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Calpain inhibition attenuates bleomycin-induced pulmonary fibrosis via switching the development of epithelial-mesenchymal transition

Liu

Zhang

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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“…This results in elevated HIF-1α expression to suppress ASS1 for synthetic lethality by ADI-PEG20. Previous studies have demonstrated that expression of DEC1 can be regulated by many environmental stimuli, including nutritional feeding [37], growth factor [38], and genotoxic agents [39, 40]. In mammalian cells, DEC1 functions as a repressor for the circadian transcriptional regulators CLOCK/BMAL through promoter E-box binding [20].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation

et al. 2016

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Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1α and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF-1α but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1α and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1α accumulation, we further demonstrated that HIF-1α is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy.

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“…The authors suggested that BHLHE40 overexpression is a protective mechanism against ESCC progression. A second study using esophageal cancer cell lines showed that BHLHE40 overexpression promoted www.Genes&Cancer.com apoptosis as indicated by an increase in PARP cleavage [86]. Thus, while IEN is characterized by an increase in BHLHE40, progression to ESCC is characterized by its decrease.…”

Section: Cancers Where Bhlhe40 Expression Is Bimodal: Esophageal Carcmentioning

confidence: 99%

“…In colon cancer, BHLHE40 overexpression impeded serum deprivationinduced apoptosis and selectively inhibited the activation of procaspases related to the intrinsic death pathway (precaspase 3, 7, 9), without affecting the extrinsic death pathway [79]. On the other hand, a study using esophageal cancer cell lines showed that BHLHE40 overexpression promoted apoptosis as indicated by an increase in PARP cleavage [86]. This contrast can be explained by investigation of the downstream targets of BHLHE40 in cancers where it either promotes or inhibits apoptosis.…”

Section: Dual Effect Of Bhlhe40 On Apoptosismentioning

confidence: 99%

Non-circadian aspects of BHLHE40 cellular function in cancer

2020

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While many genes specifically act as oncogenes or tumor suppressors, others are tumor promoters or suppressors in a context-dependent manner. Here we will review the basic-helix-loop-helix (BHLH) protein BHLHE40, (also known as BHLHB2, STRA13, DEC1, or SHARP2) which is overexpressed in gastric, breast, and brain tumors; and downregulated in colorectal, esophageal, pancreatic and lung cancer. As a transcription factor, BHLHE40 is expressed in the nucleus, where it binds to target gene promoters containing the E-box hexanucleotide sequence, but can also be expressed in the cytoplasm, where it stabilizes cyclin E, preventing cyclin E-mediated DNA replication and cell cycle progression. In different organs BHLHE40 regulates different targets; hence may have different impacts on tumorigenesis. BHLHE40 promotes PI3K/Akt/ mTOR activation in breast cancer, activating tumor progression, but suppresses STAT1 expression in clear cell carcinoma, triggering tumor suppression. Target specificity likely depends on cooperation with other transcription factors. BHLHE40 is activated in lung and esophageal carcinoma by the tumor suppressor p53 inducing senescence and suppressing tumor growth, but is also activated under hypoxic conditions by HIF-1α in gastric cancer and hepatocellular carcinomas, stimulating tumor progression. Thus, BHLHE40 is a multi-functional protein that mediates the promotion or suppression of cancer in a context dependent manner.

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<b>Basic helix-loop-helix transcription factor DEC1 regulates the cisplatin-induced apoptotic pathway of human esophageal cancer </b><b>cells </b>

Cited by 16 publications

References 23 publications

Calpain inhibition attenuates bleomycin-induced pulmonary fibrosis via switching the development of epithelial-mesenchymal transition

Calpain inhibition attenuates bleomycin-induced pulmonary fibrosis via switching the development of epithelial-mesenchymal transition

Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation

Non-circadian aspects of BHLHE40 cellular function in cancer

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