Special Issue "Close links between Cold Shock Proteins and Cancer"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 31 December 2020.

Special Issue Editors

Prof. Dr. Mahmoud Toulany
Website
Guest Editor
1. Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany
2. German Cancer Consortium (DKTK) Partnersite Tuebingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
Interests: YB-1, solid tumors, radiotherapy, DNA damage response, therapy resistance
Dr. Annette Lasham

Guest Editor
Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, PO Box 50, Auckland 1142, New Zealand, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
Interests: YB-1; cancer biomarkers; breast cancer; genomics

Special Issue Information

Dear Colleagues,

Cold shock proteins (CSPs) are the most evolutionarily-conserved nucleic acid binding proteins, and regulate a multitude of cellular functions, including proliferation, survival, and stress response. Many of these properties are considered hallmarks of cancer cells. Therefore, it is becoming increasingly acknowledged that these underrated molecules play an important role in cancer biology. DNA-binding protein-A (Dbp-A) and Y-box-binding protein-1 (YB-1; also known as Dbp-B) are the two most characterized CSPs, functioning by regulating the transcription and translation of key proteins, accelerating the repair of a wide variety of DNA damages and sorting miRNAs, to name just a few of their mechanisms of action described to date. We now know that CSPs are also secreted from cells via exosomes and the Golgi apparatus, and bind to cell surface receptors (e.g. Notch receptors) to activate intracellular signaling cascades. YB-1 also regulates the transcription of genes involved in drug resistance and malignant progression. Not surprisingly, high levels of YB-1 protein or YBX1 mRNA have been associated with poor prognosis of patients in a wide range of cancers. Thus, YB-1 has been proposed as both a biomarker and a potential therapeutic target for many cancer types.

We invite researchers in the field to contribute to this Special Issue, covering subjects that support the link between CSPs and cancer, including descriptions of the underlying signaling pathways involving CSPs or contributing to the activation of CSPs, in addition to strategies targeting CSPs or CSP-dependent signaling pathways to treat cancer and overcome therapy resistance. Furthermore, given that we live in the “omics” era, we also encourage contributions from bioinformatic analyses of large datasets to further understand the role of the CSPs in cancer.

Prof. Dr. Mahmoud Toulany
Dr. Annette Lasham
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cold shock proteins
  • Y-box-binding protein-1
  • DNA-binding protein-A
  • signaling pathways
  • therapy resistance
  • cancer
  • inflammatory disease
  • targeted therapies

Published Papers (7 papers)

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Research

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Open AccessArticle
Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers
Cancers 2020, 12(10), 2795; https://doi.org/10.3390/cancers12102795 - 29 Sep 2020
Abstract
The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways [...] Read more.
The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Open AccessArticle
Critical Role for Cold Shock Protein YB-1 in Cytokinesis
Cancers 2020, 12(9), 2473; https://doi.org/10.3390/cancers12092473 - 01 Sep 2020
Abstract
High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in [...] Read more.
High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging we found that YB-1 was essential for orchestrating the spatio-temporal distribution of the microtubules, β-actin and the chromosome passenger complex (CPC) to define the cleavage plane. We show that phosphorylation at six serine residues was essential for cytokinesis, of which novel sites were identified using mass spectrometry. Using atomistic modelling we show how phosphorylation at multiple sites alters YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining precisely how YB-1 regulates cell division. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Open AccessArticle
Tumour Progression Stage-Dependent Secretion of YB-1 Stimulates Melanoma Cell Migration and Invasion
Cancers 2020, 12(8), 2328; https://doi.org/10.3390/cancers12082328 - 18 Aug 2020
Cited by 2
Abstract
Secreted factors play an important role in intercellular communication. Therefore, they are not only indispensable for the regulation of various physiological processes but can also decisively advance the development and progression of tumours. In the context of inflammatory disease, Y-box binding protein 1 [...] Read more.
Secreted factors play an important role in intercellular communication. Therefore, they are not only indispensable for the regulation of various physiological processes but can also decisively advance the development and progression of tumours. In the context of inflammatory disease, Y-box binding protein 1 (YB-1) is actively secreted and the extracellular protein promotes cell proliferation and migration. In malignant melanoma, intracellular YB-1 expression increases during melanoma progression and represents an unfavourable prognostic marker. Here, we show active secretion of YB-1 from melanoma cells as opposed to benign cells of the skin. Intriguingly, YB-1 secretion correlates with the stage of melanoma progression and depends on a calcium- and ATP-dependent non-classical secretory pathway leading to the occurrence of YB-1 in the extracellular space as a free protein. Along with an elevated YB-1 secretion of melanoma cells in the metastatic growth phase, extracellular YB-1 exerts a stimulating effect on melanoma cell migration, invasion, and tumourigenicity. Collectively, these data suggest that secreted YB-1 plays a functional role in melanoma cell biology, stimulating metastasis, and may serve as a novel biomarker in malignant melanoma that reflects tumour aggressiveness. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Open AccessArticle
YB-1 Knockdown Inhibits the Proliferation of Mesothelioma Cells through Multiple Mechanisms
Cancers 2020, 12(8), 2285; https://doi.org/10.3390/cancers12082285 - 14 Aug 2020
Abstract
Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein that has been shown to regulate proliferation, invasion and metastasis in a variety of cancer types. We previously demonstrated that YB-1 is overexpressed in mesothelioma cells and its knockdown significantly reduces tumour cell proliferation, migration, [...] Read more.
Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein that has been shown to regulate proliferation, invasion and metastasis in a variety of cancer types. We previously demonstrated that YB-1 is overexpressed in mesothelioma cells and its knockdown significantly reduces tumour cell proliferation, migration, and invasion. However, the mechanisms driving these effects are unclear. Here, we utilised an unbiased RNA-seq approach to characterise the changes to gene expression caused by loss of YB-1 knockdown in three mesothelioma cell lines (MSTO-211H, VMC23 and REN cells). Bioinformatic analysis showed that YB-1 knockdown regulated 150 common genes that were enriched for regulators of mitosis, integrins and extracellular matrix organisation. However, each cell line also displayed unique gene expression signatures, that were differentially enriched for cell death or cell cycle control. Interestingly, deregulation of STAT3 and p53-pathways were a key differential between each cell line. Using flow cytometry, apoptosis assays and single-cell time-lapse imaging, we confirmed that MSTO-211H, VMC23 and REN cells underwent either increased cell death, G1 arrest or aberrant mitotic division, respectively. In conclusion, this data indicates that YB-1 knockdown affects a core set of genes in mesothelioma cells. Loss of YB-1 causes a cascade of events that leads to reduced mesothelioma proliferation, dependent on the underlying functionality of the STAT3/p53-pathways and the genetic landscape of the cell. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Open AccessArticle
YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation
Cancers 2020, 12(8), 2188; https://doi.org/10.3390/cancers12082188 - 05 Aug 2020
Cited by 1
Abstract
Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent [...] Read more.
Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-κB activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-κB activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Open AccessArticle
Dephosphorylation of YB-1 is Required for Nuclear Localisation During G2 Phase of the Cell Cycle
Cancers 2020, 12(2), 315; https://doi.org/10.3390/cancers12020315 - 29 Jan 2020
Cited by 1
Abstract
Elevated levels of nuclear Y-box binding protein 1 (YB-1) are linked to poor prognosis in cancer. It has been proposed that entry into the nucleus requires specific proteasomal cleavage. However, evidence for cleavage is contradictory and high YB-1 levels are prognostic regardless of [...] Read more.
Elevated levels of nuclear Y-box binding protein 1 (YB-1) are linked to poor prognosis in cancer. It has been proposed that entry into the nucleus requires specific proteasomal cleavage. However, evidence for cleavage is contradictory and high YB-1 levels are prognostic regardless of cellular location. Here, using confocal microscopy and mass spectrometry, we find no evidence of specific proteolytic cleavage. Doxorubicin treatment, and the resultant G2 arrest, leads to a significant increase in the number of cells where YB-1 is not found in the cytoplasm, suggesting that its cellular localisation is variable during the cell cycle. Live cell imaging reveals that the location of YB-1 is linked to progression through the cell cycle. Primarily perinuclear during G1 and S phases, YB-1 enters the nucleus as cells transition through late G2/M and exits at the completion of mitosis. Atomistic modelling and molecular dynamics simulations show that dephosphorylation of YB-1 at serine residues 102, 165 and 176 increases the accessibility of the nuclear localisation signal (NLS). We propose that this conformational change facilitates nuclear entry during late G2/M. Thus, the phosphorylation status of YB-1 determines its cellular location. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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Review

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Open AccessReview
The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer
Cancers 2020, 12(1), 205; https://doi.org/10.3390/cancers12010205 - 14 Jan 2020
Cited by 3
Abstract
Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR [...] Read more.
Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin. Full article
(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)
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