Regulation of the Mechanism of <i>TWIST1</i> Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Asanoma, Kazuo; Liu, Ge; Yamane, Takako; Miyanari, Yoko; Takao, Tomoka; Yagi, Hiroshi; Ohgami, Tatsuhiro; Ichinoe, Akimasa; Sonoda, Kenzo; Wake, Norio; Kato, Kiyoko

doi:10.1128/mcb.00678-15

Cited by 39 publications

(66 citation statements)

References 55 publications

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“…In addition, the similar results observed in the MDA‐MB‐231 cells indicated that the role of BHLHE40 in regulating cell migration and invasion is not restricted to MCF‐7 cells. Although our data and the results of Wu et al indicated that BHLHE40 acts as a pro‐invasion gene in breast cancer and pancreatic cancer, another study has reported an inverse function of BHLHE40 in HEC . This inconsistency remains to be clarified, and tissue specificity may be a reasonable explanation.…”

Section: Disscussioncontrasting

confidence: 78%

“…Although our data and the results of Wu et al 23 indicated that BHLHE40 acts as a pro-invasion gene in breast cancer and pancreatic cancer, another study has reported an inverse function of BHLHE40 in HEC. 22 This inconsistency remains to be clarified, and tissue specificity may be a reasonable explanation.…”

Section: Disscussionmentioning

confidence: 99%

“…4,5,13,16,17,[19][20][21] To date, few studies have discussed the role of BHLHE40 in tumor invasion or metastasis, and the results were not consistent. Kazuo et al 22 have demonstrated that BHLHE40 suppressed epithelial-to-mesenchymal transition (EMT), and therefore, invasion and metastasis in human endometrial adenocarcinoma (HEC), by suppressing the transcription of Twist through competing for the binding site with SP1. In contrast, Wu et al 23 have demonstrated that BHLHE40 promoted EMT in pancreatic cancer cells by activating Smad3 phosphorylation.…”

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confidence: 99%

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Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells

Zheng

Wang

et al. 2018

Molecular Carcinogenesis

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Basic helix-loop-helix family member e40 (BHLHE40) is located in 3p26.1 and acts as a transcriptional repressor of the circadian rhythm by suppressing the expression of the clock genes and clock-controlled genes. Recent research indicated that BHLHE40 may be involved in regulating tumor cell progression. However the mechanism by which BHLHE40 regulates the invasion and metastasis of tumor cells is unclear. Our in vitro assays showed that BHLHE40 promoted tumor cell invasion while BHLHE40 silencing by siRNA suppressed tumor cell invasion of MCF-7 cells. BHLHE40 suppressed the mRNA and protein expression of CLDN1 CLDN4 and CDH1 and promoted the expression of SNAI1 and SNAI2. Reporter assays demonstrated that BHLHE40 suppressed CLDN1 transcription but not through direct binding to the E-box motifs in the CLDN1 promoter. Further studies demonstrated BHLHE40 suppressed CLDN1 transcription by preventing the interaction between SP1 and a specific motif within the promoter region of CLDN1. BHLHE40 could not further suppress CLDN1 transactivation after SP1 siRNA transfection that is, BHLHE40-induced suppression of CLDN1 relied on SP1. Furthermore our data indicated that SP1 was a major regulator of CLDN1 transcription by binding to a specific motif that was located at -233 to -61 bp upstream of the transcription start site. Immunoprecipitation and co-localization data revealed an interaction between BHLHE40 and SP1. By constructing deletion mutants we found that the BHLH and Orange regions are both essential for the BHLHE40-SP1 interaction. BHLHE40 probably acts as an inhibitory nuclear cofactor or perhaps recruits other inhibitory cofactors to inhibit the SP1-mediated CLDN1 transactivation. These results suggest that BHLHE40 facilitates cell invasion and may be used as a novel target for breast cancer prevention and treatment.

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Section: Disscussioncontrasting

confidence: 78%

Section: Disscussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells

Zheng

Wang

et al. 2018

Molecular Carcinogenesis

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“…Our mRNA expression and bioinformatics analysis identified a large number of additional genes of the ER stress response that are induced by HCoV-229E, such as CHAC1, an enzyme that degrades glutathione [47,48] and others (FICD, HERPUD1, DNAJB9/ERDJ4) functioning as regulators of AMPylation, ubiquitylation or co-chaperones, respectively [49][50][51]. Moreover, HCoV-229E was found to upregulate transcription factors (TFs) with known functions such as EGR1 and c-JUN, but also poorly characterized TFs such as zinc finger (ZNF)165, basic helix-loop-helix-type transcription factors (BHLHE40/41) or zinc finger and BTB domain-containing 43 (ZBTB43) [52,53].…”

Section: Discussionmentioning

confidence: 99%

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

et al. 2017

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Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 229E (HCoV-229E)-infected A549 and HuH7 cells, respectively, revealing a core signature of upregulated genes in these cells. Compared to treatment with the prototypical inflammatory cytokine interleukin(IL)-1, HCoV-229E replication was found to attenuate the inducible activity of the transcription factor (TF) NF-κB and to restrict the nuclear concentration of NF-κB subunits by (i) an unusual mechanism involving partial degradation of IKKβ, NEMO and IκBα and (ii) upregulation of TNFAIP3 (A20), although constitutive IKK activity and basal TNFAIP3 expression levels were shown to be required for efficient virus replication. Second, we characterized actively transcribed genomic regions and enhancers in HCoV-229E-infected cells and systematically correlated the genome-wide gene expression changes with the recruitment of Ser5-phosphorylated RNA polymerase II and prototypical histone modifications (H3K9ac, H3K36ac, H4K5ac, H3K27ac, H3K4me1). The data revealed that, in HCoV-infected (but not IL-1-treated) cells, an extensive set of genes was activated without inducible p65 NF-κB being recruited. Furthermore, both HCoV-229E replication and IL-1 were shown to upregulate a small set of genes encoding immunomodulatory factors that bind p65 at promoters and require IKKβ activity and p65 for expression. Also, HCoV-229E and IL-1 activated a common set of 440 p65-bound enhancers that differed from another 992 HCoV-229E-specific enhancer regions by distinct TF-binding motif combinations. Taken together, the study shows that cytoplasmic RNA viruses fine-tune NF-κB signaling at multiple levels and profoundly reprogram the host cellular chromatin landscape, thereby orchestrating the timely coordinated expression of genes involved in multiple signaling, immunoregulatory and metabolic processes.

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“…Dysregulation of BHLHE41 transcription levels has been characterized as a marker of the progression of several cancers . Recent studies indicate that BHLHE41 is involved in regulating tumour migration and invasion . Asanoma et al demonstrated that BHLHE41 suppressed tumour invasion and metastasis in endometrial cancer by inhibiting TWIST1 transcription.…”

Section: Introductionmentioning

confidence: 99%

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

Zhang

Zheng

Wang

et al. 2020

J Cellular Molecular Medi

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| 4001 wileyonlinelibrary.com/journal/jcmm | INTRODUC TI ONBasic helix-loop-helix family member e41 (BHLHE41, also known as SHARP1, DEC2 and BHLHB3) is mapped to human chromosome 12p12.1. It serves an important role in regulating cell differentiation, maintaining circadian rhythm, apoptosis, hypoxia and immune response. [1][2][3][4][5][6][7][8][9][10][11] The major functions of BHLHE41 are divided into two categories: circadian and non-circadian regulation. For the former, BHLHE41 protein re-enters the nucleus after transcription and translation and competes with CLOCK-BMAL1 heterodimer for E-Box element binding (through competitive inhibition). BHLHE41 functions as a suppressor of circadian rhythm regulation in this process. 11,12 For non-circadian regulation, BHLHE41 is implicated in multiple other pathways, such as BCR, notch, hypoxia, ERK/NF-kappaB and PI3K/Akt pathways. 3,6,8,[13][14][15] Dysregulation of BHLHE41 transcription levels has been characterized as a marker of the progression of several cancers. 8,[16][17][18][19][20][21][22][23] Abstract Deregulation of the basic helix-loop-helix family member e41 (BHLHE41) has been characterized as a marker of progression of several cancers. In this study, we aimed to explore the mechanism by which BHLHE41 regulates the invasion of breast cancer cells. BHLHE41 suppresses, whereas the silencing of BHLHE41 promotes tumour invasion of both MCF-7 and MDA-MB-231 cells. Meanwhile, BHLHE41 down-regulated the transcription and translation of SNAI1, SNAI2, VIM and CDH2, and up-regulated those of CLDN1, CLDN4 and CDH1. Reporter assay indicated that silencing of BHLHE41 dramatically activated the MAPK/JNK signalling pathway in MCF-7 cell line and the hypoxia signalling pathway in MDA-MB-231 cell line. Furthermore, silencing of BHLHE41 activated the MAPK/JNK signalling pathway by up-regulating phosphorylated JNK and failed to affect the expression of HIF-1 alpha in MCF-7 cells. After blocking the MAPK/JNK signalling pathway by specific inhibitor SP600125, silencing of BHLHE41 failed to promote tumour cell invasion. These results suggest that BHLHE41 facilitates MCF-7 cell invasion mainly via the activation of MAPK/ JNK signalling pathway. In conclusion, although BHLHE41 suppresses tumour invasion in MCF-7 and MDA-MB-231 cell lines, the specific regulatory mechanisms may be different. K E Y W O R D S BHLHE41, breast cancer, invasion, JNK signalling pathway, tight junction How to cite this article: Zhang D, Zheng Q, Wang C, Zhao N, Liu Y, Wang E. BHLHE41 suppresses MCF-7 cell invasion via MAPK/JNK pathway.

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Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Cited by 39 publications

References 55 publications

Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells

Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

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