DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase

Bi, Hai-Lian; Li, S; Qu, Xiaoni; Wang, M; Bai, Xiaoyan; Xu, Zhaowei; Ao, Xiang; Jia, Zhaojun; Jiang, Xiao Bing; Yang, Yongliang; Wu, Harry X.

doi:10.1038/cddis.2015.247

Cited by 60 publications

(55 citation statements)

References 53 publications

(61 reference statements)

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“…Their expressions are positively related to histologic grade, invasion and resistance of tumors. The stable expression of cyclin E when only using α-bisabolol or radiotherapy may be due to the compensation effect of other molecular pathway [41][42][43] or the low dose we used, while it was significantly reduced when using α-bisabolol and radiotherapy together. Thus, the decrease we detected indicated that EC cells were suppressed, and the progression of EC was slowed by the combination of α-bisabolol and radiotherapy.…”

Section: Discussionmentioning

confidence: 92%

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

Fang¹,

Wang²,

Li³

et al. 2019

Bioscience Reports

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Endometrial cancer (EC) is one of the most common cancers in females. Although the diagnosis and treatment in early stages can greatly improve the survival rate of patients, the advanced EC still is lethal. Radiotherapy is widely used against EC, and it is a great challenge to find an effective way to overcome the resistance of EC during radiotherapy. α-bisabolol is a promising drug, which has already exhibited its anti-tumor effect in some malignancies. Here we reported that α-bisabolol could inhibit the proliferation of EC cells. It is also shown that their abilities of migration and invasion were effectively reduced by α-bisabolol. Furthermore, our results also demonstrated that α-bisabolol could improve sensitivity of EC cells in radiotherapy and further inhibited the growth of EC cells. By Western blot, we found the expression of matrix metalloproteinases-9 (MMP-9) and cyclin E were significantly decreased, which indicated that EC cells can be further suppressed by using α-bisabolol and radiotherapy. It is also demonstrated in our study that the rate of apoptotic cells is markedly increased in EC by using these two treatments. The significant decrease in X-linked inhibitor of apoptosis protein (XIAP) and increase in caspase-3 detected in our study suggested that the enhancement of apoptosis is mediated by XIAP/caspase-3 pathway, which was further confirmed by examining the downstream effectors of caspase-3, COX-2, PARP and cleaved PARP. In the present study, we demonstrated that α-bisabolol could enhance the sensitivity of EC cells to radiotherapy, which provide a novel alternative for overcoming radioresistance of EC cells and achieving a better outcome in radiotherapy.

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Section: Discussionmentioning

confidence: 92%

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

Fang¹,

Wang²,

Li³

et al. 2019

Bioscience Reports

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“…The function of nuclear BHLHE40 was apparent from other studies, where nuclear BHLHE40 was up-regulated in MCF-7 estrogen receptor positive breast cancer cells www.Genes&Cancer.com upon paclitaxel treatment [103], suggesting that nuclear BHLHE40 prevent tumor progression. In contrast, cytoplasmic BHLHE40 bound to and stabilized cyclin E [104], thereby preventing its nuclear entry and inhibiting cell cycle progression, thus, an increase in cytoplasmic BHLHE40 is tumor suppressive. Therefore, in these cases, despite an upregulation, BHLHE40 may not play an oncogenic role.…”

Section: Differential Effect Of Bhlhe40 In the Nucleus And The Cytoplasmmentioning

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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“…BHLHE40 has primarily been reported to be involved in multiple biological functions, such as neurogenesis, apoptosis, cell proliferation and differentiation, and circadian rhythms . Recent studies have shown the diverse expression of BHLHE40 in different tumors and indicated the tissue specificity.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 BHLHE40 has primarily been reported to be involved in multiple biological functions, such as neurogenesis, apoptosis, cell proliferation and differentiation, and circadian rhythms. [8][9][10][11][12] Recent studies have shown the diverse expression of BHLHE40 in different tumors and indicated the tissue specificity. Compared with adjacent normal tissues, higher expression levels of BHLHE40 were found in most tumors (colon, oral, gastric, pancreatic, esophageal, liver cancer, and brain tumors) except for non-small-cell lung cancer.…”

mentioning

confidence: 99%

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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DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase

Cited by 60 publications

References 53 publications

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

Non-circadian aspects of BHLHE40 cellular function in cancer

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

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