A novel epigenetic CREB‐miR‐373 axis mediates ZIP4‐induced pancreatic cancer growth

Zhang, Yuqing; Yang, Jingxuan; Cui, Xiaobo; Chen, Yong; Zhu, Vivian F.; Hagan, John P.; Wang, Huamin; Yu, Xianjun; Hodges, Sally E.; Fang, Jing; Chiao, Paul J.; Logsdon, Craig D.; Fisher, William E.; Brunicardi, F. Charles; Chen, Changyi; Yao, Qizhi; Fernández-Zapico, Martín E.; Li, Min

doi:10.1002/emmm.201302507

Cited by 92 publications

(90 citation statements)

References 30 publications

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“…[2][3][4] Despite the published availability of this clinical evidence, Li et al have maintained a conclusion that zinc is increased in pancreatic adenocarcinoma. [13][14][15][16][17] However, they have not provided any zinc measurements in human pancreatic tissues in support of their conclusion. Nor have they acknowledged in any of their reports the existence of the clinical evidence that presently contradicts their clinically unfounded conclusion.…”

Section: Discussionmentioning

confidence: 60%

The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma

Franklin

Zou

Costello

2014

Cancer Biology & Therapy

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Pancreatic cancer (ductal adenocarcinoma) remains a deadly cancer with ~85% mortality, and a 5-year survival rate of ~6% or less for the past 30 years. The factors and events associated with the development of pancreatic cancer are poorly identified. As such, effective biomarkers for early detection of malignancy are lacking. Efficacious chemotherapy once the cancer is identified does not exist. Recent clinical studies have revealed that the zinc levels are consistently and markedly decreased in adenocarcinoma as compared with normal/benign pancreatic tissue. The decreased zinc is exhibited in well-differentiated malignancy and in progressing malignancy, and also exists throughout the development of PanIN. Concurrent with the decrease in zinc, RREB1 transcription factor and ZIP3 zinc uptake transporter are downregulated. Thus, a RREB1/ZIP3/Zinc transformation appears to be an early event in the development of pancreatic cancer. We propose that this transformation is necessary to prevent the accumulation of high cellular zinc levels, which result in cytotoxic effects on the developing malignant cells. This report now demonstrates that exposure of Panc1 cells to physiological concentrations of zinc that result in increased zinc uptake and accumulation also inhibits cell proliferation. The study further shows that ZIP3 is the important transporter required for the accumulation of zinc and its inhibition of proliferation. RREB1 is identified as the positive regulator of ZIP3 expression. Therefore, the pathway of RREB1/ZIP3/Zinc and its downregulation during oncogenesis exist to prevent the accumulation of cytotoxic levels of zinc during the development and progression of the malignant cells in pancreatic adenocarcinoma.

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Section: Discussionmentioning

confidence: 60%

The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma

Franklin

Zou

Costello

2014

Cancer Biology & Therapy

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“…Aberrant expression of ZIP4 is associated with pathogenesis and progression in cancer and carcinomas (238,244,438). In the case of pancreatic cancer, ZIP4 enhances CREB activity by the uptake of zinc, which transcriptionally increases miR-373 expression, leading to silencing of molecules with tumor suppressor activity (459). High ZIP4 expression was associated with higher grade of gliomas and shorter overall survival (244).…”

Section: Zip4 (Liv-1 Subfamily)mentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

873

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…Loss of miR-9 suppresses proliferation, promotes migration of progenitor cells in vitro [51] and coordinates the proliferation of glioma cells [21]. In pancreatic cancer, the CREB-dependent induction of miR-373 promotes pancreatic tumor growth in vitro and in vivo [52]. In melanoma cells CREB has been shown to suppress the expression of the RNA-editing enzyme ADAR1 in vitro and in situ , while the restoration of its expression reduced melanoma growth and metastasis formation in vivo .…”

Section: Molecular Basis Of Creb Regulationmentioning

confidence: 99%

Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target

2016

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The cyclic AMP response element binding (CREB) protein has pleiotropic activities in physiologic processes. Due to its central position downstream of many growth signaling pathways CREB has the ability to influence cell survival, growth and differentiation of normal, but also of tumor cells suggesting an oncogenic potential of CREB. Indeed, increased CREB expression and activation is associated with tumor progression, chemotherapy resistance and reduced patients' survival. We summarize here the different cellular functions of CREB in tumors of distinct histology as well as its use as potential prognostic marker. In addition, the underlying molecular mechanisms to achieve constitutive activation of CREB including structural alterations, such as gene amplification and chromosomal translocation, and deregulation, which could occur at the transcriptional, post-transcriptional and post-translational level, will be described. Since downregulation of CREB by different strategies resulted in inhibition of cell proliferation, invasion and induction of apoptosis, the role of CREB as a promising target for cancer therapy will be also discussed.

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A novel epigenetic CREB‐miR‐373 axis mediates ZIP4‐induced pancreatic cancer growth

Cited by 92 publications

References 30 publications

The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma

The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target

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