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Cancers
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p21 – An Underestimated Driver for Cancers
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p21 – An Underestimated Driver for Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 June 2019) | Viewed by 75730

Special Issue Editor

Prof. Dr. Regine Schneider-Stock

E-Mail Website
Guest Editor
Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Universitätsstraße, Erlangen, Germany
Interests: colon cancer metastasis; CAM model; tumor cell invasion; tumor invasion front
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For the first time Gartel et al. (2009) have proposed the idea of antagonistic duality of p21 in cancer. Since nearly all cancer types have defects in cell cycle regulatory proteins a role of p21 in tumor transformation, progression, and invasion is suggested. Dependent on cellular compartment it might play a pro-apoptotic or a survival role. Here, we will collect a series of papers that show how p21 is involved in tumor aggressiveness, in stemness, chemotherapy resistance or phenotypic plasticity of tumor cells. We will show how the modulation of the mdm2-p53-p21 axis contributes to cell death. We will describe the role of p21 gene-editing tools in cancer research. Review and original articles will be presented to highlight the role of p21 in EMT and stemness. The interaction of p21 with other protein kinases and the role of this network in resistance mechanisms will be reviewed. Finally, this special issue will give an overview of the up-to-date knowledge about all fascinating facets of p21 in cancer.

Prof. Dr. Regine Schneider-Stock
Guest Editor

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 submissions that pass pre-check are 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 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 semimonthly journal published by MDPI.

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Published Papers (7 papers)

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Research

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17 pages, 14083 KiB  
Article
Function of p21 (Cip1/Waf1/CDKN1A) in Migration and Invasion of Cancer and Trophoblastic Cells
by Nina-Naomi Kreis, Alexandra Friemel, Andreas Ritter, Susanne Roth, Udo Rolle, Frank Louwen and Juping Yuan
Cancers 2019, 11(7), 989; https://doi.org/10.3390/cancers11070989 - 15 Jul 2019
Cited by 28 | Viewed by 5253
Abstract
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and [...] Read more.
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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Review

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21 pages, 1325 KiB  
Review
The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics
by Samar Al Bitar and Hala Gali-Muhtasib
Cancers 2019, 11(10), 1475; https://doi.org/10.3390/cancers11101475 - 30 Sep 2019
Cited by 152 | Viewed by 14091
Abstract
p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in [...] Read more.
p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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20 pages, 2282 KiB  
Review
Epigenetic Regulation of p21cip1/waf1 in Human Cancer
by Matthias Ocker, Samar Al Bitar, Ana Carolina Monteiro, Hala Gali-Muhtasib and Regine Schneider-Stock
Cancers 2019, 11(9), 1343; https://doi.org/10.3390/cancers11091343 - 11 Sep 2019
Cited by 29 | Viewed by 4890
Abstract
p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such [...] Read more.
p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo- and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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23 pages, 743 KiB  
Review
The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy
by Nina-Naomi Kreis, Frank Louwen and Juping Yuan
Cancers 2019, 11(9), 1220; https://doi.org/10.3390/cancers11091220 - 21 Aug 2019
Cited by 207 | Viewed by 15876
Abstract
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to [...] Read more.
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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19 pages, 628 KiB  
Review
p21 in Cancer Research
by Bahar Shamloo and Sinem Usluer
Cancers 2019, 11(8), 1178; https://doi.org/10.3390/cancers11081178 - 14 Aug 2019
Cited by 246 | Viewed by 18588
Abstract
p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor [...] Read more.
p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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17 pages, 802 KiB  
Review
p21cip1/waf1 Coordinates Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress
by Kanjoormana Aryan Manu, Pham Hong Anh Cao, Tin Fan Chai, Patrick J. Casey and Mei Wang
Cancers 2019, 11(8), 1112; https://doi.org/10.3390/cancers11081112 - 3 Aug 2019
Cited by 35 | Viewed by 6059
Abstract
Cancer cells possess metabolic properties that are different from benign cells. These unique characteristics have become attractive targets that are being actively investigated for cancer therapy. p21cip1/waf1, also known as Cyclin-Dependent Kinase inhibitor 1A, is encoded by the CDKN1A gene. It is a [...] Read more.
Cancer cells possess metabolic properties that are different from benign cells. These unique characteristics have become attractive targets that are being actively investigated for cancer therapy. p21cip1/waf1, also known as Cyclin-Dependent Kinase inhibitor 1A, is encoded by the CDKN1A gene. It is a major p53 target gene involved in cell cycle progression that has been extensively evaluated. To date, p21 has been reported to regulate various cell functions, both dependent and independent of p53. Besides regulating the cell cycle, p21 also modulates apoptosis, induces senescence, and maintains cellular quiescence in response to various stimuli. p21 transcription is induced in response to stresses, including those from oxidative and chemotherapeutic treatment. A recent study has shown that in response to metabolic stresses such as nutrient and energy depletion, p21 expression is induced to regulate various cell functions. Despite the biological significance, the mechanism of p21 regulation in cancer adaptation to metabolic stress is underexplored and thus represents an exciting field. This review focuses on the recent development of p21 regulation in response to metabolic stress and its impact in inducing cell cycle arrest and death in cancer cells. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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39 pages, 2605 KiB  
Review
Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists
by Justyna Kocik, Monika Machula, Aneta Wisniewska, Ewa Surmiak, Tad A. Holak and Lukasz Skalniak
Cancers 2019, 11(7), 1014; https://doi.org/10.3390/cancers11071014 - 19 Jul 2019
Cited by 33 | Viewed by 9280
Abstract
The protein p53, known as the “Guardian of the Genome”, plays an important role in maintaining DNA integrity, providing protection against cancer-promoting mutations. Dysfunction of p53 is observed in almost every cancer, with 50% of cases bearing loss-of-function mutations/deletions in the TP53 gene. [...] Read more.
The protein p53, known as the “Guardian of the Genome”, plays an important role in maintaining DNA integrity, providing protection against cancer-promoting mutations. Dysfunction of p53 is observed in almost every cancer, with 50% of cases bearing loss-of-function mutations/deletions in the TP53 gene. In the remaining 50% of cases the overexpression of HDM2 (mouse double minute 2, human homolog) protein, which is a natural inhibitor of p53, is the most common way of keeping p53 inactive. Disruption of HDM2-p53 interaction with the use of HDM2 antagonists leads to the release of p53 and expression of its target genes, engaged in the induction of cell cycle arrest, DNA repair, senescence, and apoptosis. The induction of apoptosis, however, is restricted to only a handful of p53wt cells, and, generally, cancer cells treated with HDM2 antagonists are not efficiently eliminated. For this reason, HDM2 antagonists were tested in combinations with multiple other therapeutics in a search for synergy that would enhance the cancer eradication. This manuscript aims at reviewing the recent progress in developing strategies of combined cancer treatment with the use of HDM2 antagonists. Full article
(This article belongs to the Special Issue p21 – An Underestimated Driver for Cancers)
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