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Close links between Cold Shock Proteins and Cancer

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 46873

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Prof. Dr. Mahmoud Toulany

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Guest Editor

Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany
Interests: YB-1; solid tumors; radiotherapy; DNA damage response; therapy resistance

Dr. Annette Lasham

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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

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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 semimonthly journal published by MDPI.

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Keywords

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

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 173 KiB

Open AccessEditorial

Close Links between Cold Shock Proteins and Cancer

by Mahmoud Toulany and Annette Lasham

Cancers 2023, 15(9), 2421; https://doi.org/10.3390/cancers15092421 - 23 Apr 2023

Viewed by 1322

Abstract

Nine of the ten papers published in this Special Issue explore various aspects of the multifunctional protein Y-box binding protein-1 (YB-1) and its role in cancer [...] Full article

(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)

Research

Jump to: Editorial, Review

17 pages, 4052 KiB

Open AccessArticle

Autoantibody Formation and Mapping of Immunogenic Epitopes against Cold-Shock-Protein YB-1 in Cancer Patients and Healthy Controls

by Ronnie Morgenroth, Charlotte Reichardt, Johannes Steffen, Stefan Busse, Ronald Frank, Harald Heidecke and Peter R. Mertens

Cancers 2020, 12(12), 3507; https://doi.org/10.3390/cancers12123507 - 25 Nov 2020

Cited by 6 | Viewed by 1906

Abstract

Cold shock Y-box binding protein-1 participates in cancer cell transformation and mediates invasive cell growth. It is unknown whether an autoimmune response against cancerous human YB-1 with posttranslational protein modifications or processing develops. We performed a systematic analysis for autoantibody formation directed against conformational and linear epitopes within the protein. Full-length and truncated recombinant proteins from prokaryotic and eukaryotic cells were generated. Characterization revealed a pattern of spontaneous protein cleavage, predominantly with the prokaryotic protein. Autoantibodies against prokaryotic, but not eukaryotic full-length and cleaved human YB-1 protein fragments were detected in both, healthy volunteers and cancer patients. A mapping of immunogenic epitopes performed with truncated E. coli-derived GST-hYB-1 proteins yielded distinct residues in the protein N- and C-terminus. A peptide array with consecutive overlapping 15mers revealed six distinct antigenic regions in cancer patients, however to a lesser extent in healthy controls. Finally, a protein cleavage assay was set up with recombinant pro- and eukaryotic-derived tagged hYB-1 proteins. A distinct cleavage pattern developed, that is retarded by sera from cancer patients. Taken together, a specific autoimmune response against hYB-1 protein develops in cancer patients with autoantibodies targeting linear epitopes. Full article

(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)

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19 pages, 2442 KiB

Open AccessArticle

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

by Aadhya Tiwari, Mari Iida, Corinna Kosnopfel, Mahyar Abbariki, Apostolos Menegakis, Birgit Fehrenbacher, Julia Maier, Martin Schaller, Sara Y. Brucker, Deric L. Wheeler, Paul M. Harari, Ulrich Rothbauer, Birgit Schittek, Daniel Zips and Mahmoud Toulany

Cancers 2020, 12(10), 2795; https://doi.org/10.3390/cancers12102795 - 29 Sep 2020

Cited by 16 | Viewed by 2566

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 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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29 pages, 4916 KiB

Open AccessArticle

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

by Sunali Mehta, Michael Algie, Tariq Al-Jabry, Cushla McKinney, Srinivasaraghavan Kannan, Chandra S Verma, Weini Ma, Jessie Zhang, Tara K. Bartolec, V. Pragathi Masamsetti, Kim Parker, Luke Henderson, Maree L Gould, Puja Bhatia, Rhodri Harfoot, Megan Chircop, Torsten Kleffmann, Scott B Cohen, Adele G Woolley, Anthony J Cesare and Antony Braithwaite Show full author list Hide full author list

Cancers 2020, 12(9), 2473; https://doi.org/10.3390/cancers12092473 - 01 Sep 2020

Cited by 13 | Viewed by 4996

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 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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18 pages, 13824 KiB

Open AccessArticle

Tumour Progression Stage-Dependent Secretion of YB-1 Stimulates Melanoma Cell Migration and Invasion

by Corinna Kosnopfel, Tobias Sinnberg, Birgit Sauer, Heike Niessner, Alina Muenchow, Birgit Fehrenbacher, Martin Schaller, Peter R. Mertens, Claus Garbe, Basant Kumar Thakur and Birgit Schittek

Cancers 2020, 12(8), 2328; https://doi.org/10.3390/cancers12082328 - 18 Aug 2020

Cited by 17 | Viewed by 3043

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 (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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21 pages, 4248 KiB

Open AccessArticle

YB-1 Knockdown Inhibits the Proliferation of Mesothelioma Cells through Multiple Mechanisms

by Thomas G. Johnson, Karin Schelch, Kaitao Lai, Kamila A. Marzec, Marina Kennerson, Michael Grusch, Glen Reid and Andrew Burgess

Cancers 2020, 12(8), 2285; https://doi.org/10.3390/cancers12082285 - 14 Aug 2020

Cited by 7 | Viewed by 3541

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, 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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12 pages, 2934 KiB

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YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation

by Aneri Shah, Carlos Plaza-Sirvent, Sönke Weinert, Jörn H. Buchbinder, Inna N. Lavrik, Peter R. Mertens, Ingo Schmitz and Jonathan A. Lindquist

Cancers 2020, 12(8), 2188; https://doi.org/10.3390/cancers12082188 - 05 Aug 2020

Cited by 10 | Viewed by 5167

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 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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21 pages, 5134 KiB

Open AccessArticle

Dephosphorylation of YB-1 is Required for Nuclear Localisation During G₂ Phase of the Cell Cycle

by Sunali Mehta, Cushla McKinney, Michael Algie, Chandra S. Verma, Srinivasaraghavan Kannan, Rhodri Harfoot, Tara K. Bartolec, Puja Bhatia, Alistair J. Fisher, Maree L. Gould, Kim Parker, Anthony J. Cesare, Heather E. Cunliffe, Scott B. Cohen, Torsten Kleffmann, Antony W. Braithwaite and Adele G. Woolley

Cancers 2020, 12(2), 315; https://doi.org/10.3390/cancers12020315 - 29 Jan 2020

Cited by 17 | Viewed by 4514

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 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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13 pages, 1036 KiB

Open AccessReview

Novel Insights into YB-1 Signaling and Cell Death Decisions

by Aneri Shah, Jonathan A. Lindquist, Lars Rosendahl, Ingo Schmitz and Peter R. Mertens

Cancers 2021, 13(13), 3306; https://doi.org/10.3390/cancers13133306 - 01 Jul 2021

Cited by 11 | Viewed by 3961

Abstract

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy. Full article

(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)

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22 pages, 4601 KiB

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Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

by Udo Heinemann and Yvette Roske

Cancers 2021, 13(2), 190; https://doi.org/10.3390/cancers13020190 - 07 Jan 2021

Cited by 31 | Viewed by 3759

Abstract

The cold-shock domain has a deceptively simple architecture but supports a complex biology. It is conserved from bacteria to man and has representatives in all kingdoms of life. Bacterial cold-shock proteins consist of a single cold-shock domain and some, but not all are induced by cold shock. Cold-shock domains in human proteins are often associated with natively unfolded protein segments and more rarely with other folded domains. Cold-shock proteins and domains share a five-stranded all-antiparallel β-barrel structure and a conserved surface that binds single-stranded nucleic acids, predominantly by stacking interactions between nucleobases and aromatic protein sidechains. This conserved binding mode explains the cold-shock domains’ ability to associate with both DNA and RNA strands and their limited sequence selectivity. The promiscuous DNA and RNA binding provides a rationale for the ability of cold-shock domain-containing proteins to function in transcription regulation and DNA-damage repair as well as in regulating splicing, translation, mRNA stability and RNA sequestration. Full article

(This article belongs to the Special Issue Close links between Cold Shock Proteins and Cancer)

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18 pages, 3776 KiB

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The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

by Monika Sobočan, Suzana Bračič, Jure Knez, Iztok Takač and Johannes Haybaeck

Cancers 2020, 12(1), 205; https://doi.org/10.3390/cancers12010205 - 14 Jan 2020

Cited by 22 | Viewed by 4711

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 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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