BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells

Wu, Yunyan; Sato, Fuyuki; Bhawal, Ujjal K.; Kawamoto, Takeshi; Fujimoto, Katsumi; Noshiro, Mitsuhide; Seino, Hiroko; Morohashi, Satoko; Kato, Yukio; Kijima, Hiroshi

doi:10.2220/biomedres.33.75

Cited by 31 publications

(37 citation statements)

References 28 publications

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“…This is also consistent with previous findings (17). Although the mechanism underlying the upregulated expression of BHLHE41 in the process of carcinogenesis has not been elucidated, several studies have indicated that BHLHE41 suppresses apoptosis and enhances genomic instability (25,(44)(45)(46). These findings suggest that the upregulated expression of BHLHE41 is expedient for carcinogenesis in endometrial epithelial cells.…”

Section: Discussionsupporting

confidence: 92%

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

Asanoma

Liu

Yamane

et al. 2015

Molecular and Cellular Biology

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c BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors SNAI1, SNAI2, and TWIST1. We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression. Basic helix-loop-helix (bHLH) type transcription factors play key roles in cell differentiation, proliferation, apoptosis, and metabolism. BHLHE40 (basic helix-loop-helix family member e40 gene) and BHLHE41 are members of the Hairy/E(spl)/HES family. BHLHE40 and BHLHE41 (BHLHE40/41) exhibit more than 90% similarity in the bHLH region and approximately 50% in total. BHLHE40/41 have been shown to function as transcriptional repressors by binding to the class B E-box. BHLHE40/41 interact with TF2B, TBP, or TF2D or recruit a histone deacetylase at the E-box site (1-5). On the other hand, BHLHE40/41 were previously reported to modulate the expression of some genes in an E-box-independent manner. BHLHE40 has been shown to associate with SP1 binding sites in the BIRC5 promoter to activate its transcription (6) and with STAT3 to regulate the transcription of STAT3-dependent target genes (7). BHLHE41 suppressed VEGF transcription by interacting with HIF1A (8). BHLHE40 and BHLHE41 were reported to associate with retinoid X receptor (RXR), MYOD1, or CEBP in order to regulate the transcription of their target genes (9-12).In diverse types of cancer species, such as colon, oral, and liver cancer or brain tumors, BHLHE40 expression levels were found to be higher in tumors than in adjacent normal tissues (13-15). On the other hand, in human endometrial cancer (HEC) and nonsmall-cell lung cancer, no changes in BHLHE40 expression were reported between cancer and normal tissues (16,17). Regarding expression profiles with the development of cancer, studies on oral, lung, liver, and esophageal cancer showed that BHLHE40 expression inversely correlated with the tumor stage or differentiation grade (18-21)...

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Section: Discussionsupporting

confidence: 92%

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

Asanoma

Liu

Yamane

et al. 2015

Molecular and Cellular Biology

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“…SHARP1 is a basic helix-loop-helix transcription factor that is involved in a number of cellular processes, including proliferation [9], apoptosis [30,31], differentiation [32], and circadian rhythms [33-35]. SHARP1 is generally believed to act as a tumor suppressor, and Montagner, et al [11] recently showed that SHARP1 regulates the invasive and metastatic phenotype of triple-negative breast cancer cells by promoting degradation of hypoxia-inducible factors.…”

Section: Discussionmentioning

confidence: 99%

Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer

Liao

Qiu

et al. 2014

BMC Cancer

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BackgroundMechanisms governing the metastasis of endometrial cancer (EC) are poorly defined. Recent data support a role for Enhancer-of-split and hairy-related protein 1 (SHARP1), a basic helix-loop-helix transcription repressor, in regulating invasiveness and angiogenesis of several human cancers. However, the role of SHARP1 in metastasis of EC remains unclear.MethodsHuman EC cell lines (Ishikawa and HEC-1B) were used. SHARP1 was upregulated by lentivirus transduction, while intracellular domain of NOTCH1 (ICN) were upregulated by transient transfection with plasmids. Effects of SHARP1 on cell migration and invasion were evaluated by wound healing assay and transwell invasion assay. Experimental metastasis assay were performed in nude mice. Effects of SHAPR1 on protein levels of target genes were detected by western blotting. Furthermore, the association between SHARP1 and the NOTCH1/EMT pathway was further verified in EC tissue specimens by immunohistochemical analysis.ResultsOverexpression of SHARP1 in EC cells inhibited cell migration, invasion, and metastasis. Exogenous SHARP1 overexpression affected the proteins levels of genes involved in EMT process and NOTCH1 signaling pathway. Upregulation of ICN in SHARP1-overexpressing Ishikawa cells induced cell migration and an EMT phenotype. Additionally, immunohistochemical analysis demonstrated that SHARP1 protein levels were lower in metastatic EC than in primary tumors, and statistical analysis revealed correlations between levels of SHARP1 and markers of EMT and NOTCH1 signaling pathway in human EC tissue specimen.ConclusionsThis work supports a role for SHARP1 in suppressing EMT and metastasis in EC by attenuating NOTCH1 signaling. Therefore, SHARP1 may be a novel marker for lymphatic metastasis in EC patients.

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“…Thus, we proposed that different effects on the DEC1-related apoptosis may depend on the differences in cellular differentiation (TE 10 cells and MCF-7 cells are well-differentiated carcinoma; and TE 5 cells are poorly differentiated type). Our previous reports showed that DEC2 has antiapoptotic effects in human oral cancer HSC-3 and human breast cancer MCF-7 (23,24). Furthermore, DEC1 and DEC2 had opposite effects on apoptosis in MCF-7; i.e., we speculated that a balance between DEC1 and DEC2 may contribute to the apoptotic pathways.…”

Section: Apoptotic Effects In Cddp-treated Te 10 Cells By Dec1 Knockdmentioning

confidence: 80%

“…We analyzed the effects of CDDP on DEC1/DEC2 apoptosis in human oral squamous cell carcinoma CA9-22 and HSC-3 cells, and showed that DEC2 has anti-apoptotic effects on CDDP-induced apoptosis in HSC-3 cells involving Bim down-regulation (24). We also showed that DEC1 and DEC2 have opposite properties in regulating apoptosis, i.e., DEC2 has anti-apoptotic, whereas DEC1 has proapoptotic effects on human breast cancer MCF-7 cells (15,23).…”

Section: Effects Of Cddp On Dec1/dec2 Expressions In Te 10 and Te 5 Cmentioning

confidence: 99%

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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>

Seino

Morohashi

et al. 2015

Biomed. Res.

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DEC1[basic helix-loop-helix (BHLH) E40/Stra13/Sharp2] and DEC2 (BHLHE41/Sharp1) are BHLH transcription factors that are associated with the regulation of apoptosis, cell proliferation, and circadian rhythms, as well as malignancy in various cancers. However, the roles of DEC1 and DEC2 expression in esophageal cancer are poorly understood. In this study, we examined the roles of DEC1 and DEC2 in human esophageal cancer TE 5 and TE 10 cells that had been treated with cis-diamminedichloroplatinum (II) (cisplatin: CDDP). Expression of DEC1 and DEC2 was decreased with CDDP treatment in TE 5 cells; however, knockdown or overexpression of DEC1/ DEC2 had little effects on CDDP-induced apoptosis in TE 5 cells. DEC1 expression was up-regulated in CDDP-treated TE 10 cells, whereas DEC2 expression was unchanged. DEC1 knockdown by siRNA in TE 10 decreased the amount of cleaved poly (ADP-ribose) polymerase (PARP) after treatment with CDDP, whereas DEC2 knockdown had no effects on the amount of cleaved PARP in both the presence and absence of CDDP. We also demonstrated that DEC1 overexpression promoted cleaved PARP expression, whereas DEC2 overexpression had no effects on the amount of cleaved PARP in TE 10 cells. These results suggested that DEC1 has pro-apoptotic effects on human esophageal cancer TE 10 cells of well-differentiated type.Esophageal cancer is the eighth most common cancer worldwide, and the sixth most common cause of death from cancer in 2012 (8). Squamous cell carcinoma is one of the most prevalent histological types of esophageal cancer. Traditionally, esophageal squamous cell carcinoma (ESCC) has been treated by multimodality therapies, including surgery, radiation, and chemotherapy. Recently, preoperative chemotherapy followed by radical esophagectomy has been the standard therapeutic approach to operable ESCC (1). CDDP (cisplatin) is a well-known anticancer agent clinically used for the treatment of various malignant tumors. CDDP regulates DNA repair, transcription inhibition, cell cycle arrest, and apoptosis induced by the expression of mitogen-activated protein kinases (MAPKs), p53, Bax, Bcl-2, Bcl-xL, Bim, caspases, and the cleavage of poly (ADPribose) polymerase (PARP) (4,6,12,(19)(20)(21)26). DEC1 [basic helix-loop-helix (BHLH) E40/Stra13/ Sharp2] and DEC2 (BHLHE41/Sharp1) are members of the BHLH superfamily of transcription factors that are related to the regulation of apoptosis, cell proliferation, circadian rhythms, and the response to hypoxia (11,15,23). DEC1 is overexpressed in the tumor tissues of breast, colon, and oral cancers (3,5,14). Previously, we investigated the role of DEC1 and DEC2 in CDDP-induced

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BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells

Cited by 31 publications

References 28 publications

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

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

Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer

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

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