ME1 promotes basal-like breast cancer progression and associates with poor prognosis

Liao, Ruocen; Ren, Guoping; Liu, Huixin; Chen, Xingyu; Cao, Qianhua; Wu, Xuebiao; Li, Jun; Dong, Chenfang

doi:10.1038/s41598-018-35106-y

Cited by 44 publications

(39 citation statements)

References 36 publications

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“…Previous study of ME1 in breast cancer only focusing on TNBC subtype drew the same conclusion as ours that ME1 was highly expressed in TNBC cells, 14 but its upstream upregulators have not been reported yet. We also found the relationship between ME1 expression and HER2 positive in Curtis Breast Dataset.…”

Section: Discussionsupporting

confidence: 72%

<p>Malic Enzyme 1 Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species</p>

Liu¹,

Cao²,

Lin³

et al. 2020

OTT

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Malic enzyme 1 (ME1) catalyzes malate to pyruvate and thus promotes glycolysis. Its function in breast cancer remains to be fully clarified. The aim of this work was to investigate the prognostic value of ME1 and its possible mechanism in breast cancer. Methods: We evaluated ME1 expression in 220 early breast cancer patients with tissue microarray-based immunohistochemistry and explored the relationships between ME1 expression and clinicopathological features. Survival analyses were further performed to determine its prognostic value. The public database was used to confirm tissue microarray results. Further, cell proliferation, migration, invasion ability and reactive oxygen species (ROS) were examined in breast cancer cells. Results: In breast cancer tissues, high ME1 expression was significantly associated with larger tumor size, higher incidence of lymph node metastasis and higher incidence of lymphvascular invasion. High ME1 expression significantly correlated with worse recurrence-free survival (RFS), and was an independent prognostic factor for RFS, which was confirmed by mRNA results in the public database. In vitro, upregulation of ME1 by transfecting MCF-7 cells with virus vector remarkably enhanced viability, motility and epithelial-mesenchymal transition (EMT) and decreased ROS levels, whereas knockdown in MDA-MB-468 cells produced totally opposite effects as expected. When pretreated with oxidizing agent, MCF-7 cells overexpressing ME1 lost its motility, whereas MDA-MB-468 cells with knockdown of ME1 restored its motility when pretreated with antioxidant. Conclusion: To our knowledge, these clinical and experiment works first suggested that ME1 may be a novel biomarker and potential therapeutic target for breast cancer metastasis, and its biological effect is mainly controlled by manipulating ROS.

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Section: Discussionsupporting

confidence: 72%

<p>Malic Enzyme 1 Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species</p>

Liu¹,

Cao²,

Lin³

et al. 2020

OTT

View full text Add to dashboard Cite

show abstract

“…Previous study of ME1 in breast cancer only focusing on TNBC subtype drew the same conclusion as ours that ME1 was high expressed in TNBC cells (15), but its upstream up-regulators have not been reported yet. We also found the relationship between ME1 expression and HER2 positive in Curtis Breast Dataset.…”

Section: Discussionsupporting

confidence: 74%

“…Although ME1 is reported to enhance cell proliferation and metastasis capacity in multiple cancer types (10,11,15,17), the underlying mechanism of which still remains inexplicit. On one hand, ME1 catalyzes malate to pyruvate, inducing cell glucose uptake and lactate production and thus promote Warburg effect, which is favorable for tumor (15) As far as we know, there is still no anti-tumor drugs targeting ME1. Considering the important role of ME1 in tumor progression, we also reflect on whether ME1 is a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Malic enzyme 1 may be a novel target of breast cancer metastasis

Liu¹,

Lin²,

Zhao³

et al. 2019

Preprint

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Background Malic enzyme 1 (ME1) catalyzes malate to pyruvate and thus promotes glycolysis, playing a part in the Warburg effect. It also has a potential role in tumor progression, but its function in breast cancer remains to be fully clarified. This work aimed to investigate the prognostic value of ME1 and its possible mechanism in breast cancer.Methods We evaluated ME1 expression in 220 early breast cancer patients with tissue microarray-based immunohistochemistry and explored the relationships between ME1 expression and clinicopathological features. Survival analyses were further performed to determine its prognostic value. The public database was used to confirm tissue microarray results. Moreover, we profiled ME1 expression in breast cancer cell lines via western blotting, and then assessed it in cell viability and motility via Cell counting kit-8 (CCK-8), colony formation, transwell migration and invasion assays. Reactive oxygen species (ROS) was detected by dihydroethidium (DHE) and 2’,7’-Dichlorodihydrofluorescein diacetate (DCFH-DA).Results In breast cancer tissues, high ME1 expression was significantly associated with larger tumor size, more lymph node metastasis and more extensive lymph-vascular invasion. Survival analysis showed high ME1 expression was significantly correlated with worse recurrence free survival (RFS). Multivariate analysis further identified high ME1 expression as an independent prognostic factor for RFS, which was confirmed by mRNA results in the public database. In vitro , human epidermal growth factor receptor-2 positive and triple negative breast cancer cell lines showed higher expression of ME1, while Luminal cell lines showed lower expression of ME1. Upregulation of ME1 by transfecting MCF-7 cells with virus vector remarkably enhanced viability and motility, epithelial-mesenchymal transition (EMT), and decreased ROS levels, whereas knockdown of this gene in MDA-MB-468 cells produced totally opposite effects as expected. More important, when pretreated with hydrogen peroxide, an oxidizing agent, MCF-7 cells overexpressing ME1 lost its motility, whereas MDA-MB-468 cells with knock-down of ME1 restored its motility when pretreated with N-acetyl cysteine, an antioxidant.Conclusions To our knowledge, these clinical and experiment work first suggested that ME1 may be a potential therapeutic target for breast cancer metastasis, and its biological effect is mainly controlled by manipulating ROS.

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“…It has been reported that Nrf2 is involved in the expression of antiapoptotic proteins, promotes chemotherapy tolerance of liver cancer, and is associated with the expression of Bcl-xl, an antiapoptotic gene [35]. In addition, it has been observed that ME1 expression is positively correlated with larger tumour size, higher grade, poorer survival, and chemotherapy resistance in breast cancer patients [36]. In the present study, knockdown of Keap1 under fasting conditions resulted in enhanced cell viability, the inhibition of apoptosis and ROS accumulation, and increased expression of Nrf2/ARE signalling pathway components ( Supplementary Figures S1A-C).…”

Section: Discussionmentioning

confidence: 99%

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

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ME1 promotes basal-like breast cancer progression and associates with poor prognosis

Cited by 44 publications

References 36 publications

<p>Malic Enzyme 1 Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species</p>

<p>Malic Enzyme 1 Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species</p>

Malic enzyme 1 may be a novel target of breast cancer metastasis

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

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