Hes1: a key role in stemness, metastasis and multidrug resistance

Liu, Zi-Hao; Dai, Xiaomeng; Du, Bin

doi:10.1080/15384047.2015.1016662

Cited by 164 publications

(125 citation statements)

References 92 publications

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“…Cross-referencing of the RNA-seq and BRD4 ChIP-seq revealed that BRD4 direct target genes regulated by JQ1 treatment are significantly enriched for putative stem-related genes (Figure 4B–C and S4C–D). We validated three genes known to be implicated in CSCs, namely LIF (31), HES1 (32) and WNT5A (33), as direct BRD4 targets that are downregulated by JQ1 (Figure 4D–E and Figure S4E). This observation correlated with a decrease in the association of BRD4 and RNA polymerase II with the promoter regions of these genes after JQ1 treatment (Figure 4F).…”

Section: Resultsmentioning

confidence: 98%

BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer

et al. 2016

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The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here we show that bromodomain and extra-terminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. The clinically applicable small molecule BET inhibitor JQ1 suppressed the outgrowth of cisplatin-treated ovarian cancer cells both in vitro and in vivo. Combination of JQ1 and cisplatin improved the survival of ovarian cancer bearing mice in an orthotopic model. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and other stem-related genes in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using clinically applicable small molecule inhibitors such as JQ1 is a promising strategy for targeting ALDH activity in epithelial ovarian cancer.

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Section: Resultsmentioning

confidence: 98%

BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer

et al. 2016

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“…For instance, our previous study demonstrated that Hes1 is upregulated in OSCC, and the suppression of Hes1 in oral cancer cells inhibits self-renewal capacity of OSCC, suggesting the important role of Hes1 in OSCC CSC [55]. In addition, other reports also revealed the crucial roles of Hes1 in the maintenance of CSC properties, such as metastasis, chemotherapy resistance, and EMT [56]. Zeb1 and Zeb2 are significantly increased in head and neck CSCs compared to non-CSCs [57].…”

Section: Discussionmentioning

confidence: 99%

Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma

Lee¹,

Rigas²,

Lee³

et al. 2016

Oncotarget

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Emerging evidence indicates that Orai1, a key calcium channel for store-operated Ca2+ entry, is associated with human cancer. However, the underlying mechanism by which Orai1 regulates cancer progression remains unknown. Here we report that intracellular level of Orai1 is increased in a stepwise manner during oral/oropharyngeal carcinogenesis and highly expressed in cancer stem-like cell (CSC)-enriched populations of human oral/oropharyngeal squamous cell carcinoma (OSCC). Ectopic Orai1 expression converted non-tumorigenic immortalized oral epithelial cells to malignant cells that showed CSC properties, e.g., self-renewal capacity, increased ALDH1HIGH cell population, increased key stemness transcription factors, and enhanced mobility. Conversely, inhibition of Orai1 suppressed tumorigenicity and CSC phenotype of OSCC, indicating that Orai1 could be an important element for tumorigenicity and stemness of OSCC. Mechanistically, Orai1 activates its major downstream effector molecule, NFATc3. Knockdown of NFATc3 in the Orai1-overexpressing oral epithelial cells abrogates the effect of Orai1 on CSC phenotype. Moreover, antagonist of NFAT signaling also decreases CSC phenotype, implying the functional importance of Orai1/NFAT axis in OSCC CSC regulation. Our study identifies Orai1 as a novel molecular determinant for OSCC progression by enhancing cancer stemness, suggesting that inhibition of Orai1 signaling may offer an effective therapeutic modality against OSCC.

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“…The mechanism of Hes-1 to induce the development of T-ALL was by increasing the expression of c-myc and Nrarp which is an oncogene [23]. Hes-1 also has a role in the development of several kinds of cancer by maintaining cancer's stem cell, inducing metastasis and resistance of some antitumor drugs [10]. Hes-1 transduction followed by high expression of BCR-ABL could increase the expansion of myeloid progenitor cells in vitro and in vivo [12].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies using in vitro and in vivo in mice model approaches indicated that Hes-1 is overexpress in blast crisis CML phenotype. Hes-1 overexpression is assumed to inhibit CEBPA expression result in the blocking of myeloid differentiation [9][10][11][12]. However, there are still lacks of evidence of these conditions in humans.…”

Section: Introductionmentioning

confidence: 99%

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HES-1 and CEBPA mRNA in Chronic and Late Phase (accelerated and blast crisis) of Chronic Myeloid Leukemia (CML) Patients

Rahmawati¹,

Fatmawati²,

Purwanto³

et al. 2017

J Leuk

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Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder of hematopoietic , characterized by Philadelphia chromosome containing BCR-ABL fusion gene. The gene encodes protein with constitutive tyrosine kinase activity result in myeloid proliferation and leads to form an early phase of CML called chronic phase. Unsuccessful treatment will lead to progression of the disease into late phase (accelerated and blast crisis). The mechanisms involving disease progression are still poorly understood. It is assumed that additional genetic event involves in differentiation blocking of myeloid progenitor cells, such as Hes-1 overexpression and CEBPA down regulation. However, study on the expression of these genes in CML patient's samples is still limited. This study aims to measure Hes-1 and CEBPA mRNA in chronic and late phase of CML patients. The peripheral blood mRNA level of Hes-1 was measured in CML patient's sample with BCR-ABL positive both in chronic phase (n=61) and late phase (n=17) using qRT-PCR with GAPDH as internal control. Hes-1 mRNA was statistically higher (p value=0.0) in the chronic phase (mean ± SD=97.8 ± 236.6) compared to those in late phase (mean ± SD=8.5 ± 30.7). In addition, even though CEBPA expression in chronic and late phase were not statistically different (p value=0.1), those in chronic phase (mean ± SD=5.2 ± 16.0) were generally higher compared to those in late phase (mean ± SD=1.7 ± 2.4). Hes-1 expression upregulated in 70.5% of chronic phase patients and in 17.6% of late phase patients, whereas CEBPA expression down regulated in 42.6% of chronic phase patients and in 47.1% in late phase patients. High standard deviation, particularly in mRNA Hes-1 gene expression measurement of the chronic phase, indicated the presence of individual variations in the sample that might be influenced by other genetic factors. This study found that Hes-1 mRNA is significantly higher in peripheral blood of chronic phase than blast crisis CML, whereas CEBPA mRNA is not different.

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Hes1: a key role in stemness, metastasis and multidrug resistance

Cited by 164 publications

References 92 publications

BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer

BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer

Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma

HES-1 and CEBPA mRNA in Chronic and Late Phase (accelerated and blast crisis) of Chronic Myeloid Leukemia (CML) Patients

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