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Tumour Suppressor Function
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Tumour Suppressor Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (10 January 2020) | Viewed by 38541

Special Issue Editor

Dr. Charles Bailey

E-Mail Website
Guest Editor
Group Leader, Cancer & Gene Regulation Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
Interests: gene regulation; transcription factor biology; cancer biology; cancer genetics; chromatin organisation; disease models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumour suppressor genes act as a vanguard against the development and progression of cancer. Tumour suppressor genes are recurrently mutated in human cancers, removing important blockades on uncontrolled cellular growth such as cell cycle checkpoints, apoptosis, and DNA repair. The tumour suppressor function has been revealed from the analysis of specific genes or genetic pathways in human cancers and validated with complementary in vitro cell models and in vivo tumour xenograft studies. More recently, detailed analysis of the molecular genetic landscapes of human cancers using genomic, transcriptomic, and epigenetic techniques has revealed unexpected tumour suppressor gene functions, often in a tissue- or subset-specific fashion. Moreover, CRISPR/Cas9-based genetic screens often highlight entire pathways or signalling cascades that augment the tumour suppressor gene function.

Submission to this Special Issue, “Tumour Suppressor Function”, may include focussed molecular genetic studies in specific human cancers, the application of innovative techniques or approaches to reveal new tumour suppressor gene roles, genetic or chemical screens exploiting vulnerabilities in tumour suppressor gene-mutant cancers, or reviews offering new insights into tumour suppressor gene function in cancer.

Dr. Charles G Bailey
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 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • tumour suppressor gene
  • human cancers
  • cell cycle checkpoints
  • apoptosis
  • DNA repair
  • metastasis
  • epigenetic regulation
  • CRISPR/Cas9
  • genetic screen
  • chemical screen

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Related Special Issue

Published Papers (7 papers)

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Research

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17 pages, 3181 KiB  
Article
Isoform-Specific Lysine Methylation of RORα2 by SETD7 Is Required for Association of the TIP60 Coactivator Complex in Prostate Cancer Progression
by Hyerin Song, Jung Woong Chu, Su Chan Park, Hyuntae Im, Il-Geun Park, Hyunkyung Kim and Ji Min Lee
Int. J. Mol. Sci. 2020, 21(5), 1622; https://doi.org/10.3390/ijms21051622 - 27 Feb 2020
Cited by 13 | Viewed by 4181
Abstract
The retinoid acid-related orphan receptor α (RORα), a member of the orphan nuclear receptor superfamily, functions as an unknown ligand-dependent transcription factor. RORα was shown to regulate a broad array of physiological processes such as Purkinje cell development in the cerebellum, circadian rhythm, [...] Read more.
The retinoid acid-related orphan receptor α (RORα), a member of the orphan nuclear receptor superfamily, functions as an unknown ligand-dependent transcription factor. RORα was shown to regulate a broad array of physiological processes such as Purkinje cell development in the cerebellum, circadian rhythm, lipid and bone metabolism, inhibition of inflammation, and anti-apoptosis. The human RORα gene encodes at least four distinct isoforms (RORα1, -2, -3, -4), which differ only in their N-terminal domain (NTD). Two isoforms, RORα2 and 3, are not expressed in mice, whereas RORα1 and 4 are expressed both in mice and humans. In the present study, we identified the specific NTD of RORα2 that enhances prostate tumor progression and proliferation via lysine methylation-mediated recruitment of coactivator complex pontin/Tip60. Upregulation of the RORα2 isoform in prostate cancers putatively promotes tumor formation and progression. Furthermore, binding between coactivator complex and RORα2 is increased by lysine methylation of RORα2 because methylation permits subsequent interaction with binding partners. This methylation-dependent activation is performed by SET domain containing 7 (SETD7) methyltransferase, inducing the oncogenic potential of RORα2. Thus, post-translational lysine methylation of RORα2 modulates oncogenic function of RORα2 in prostate cancer. Exploration of the post-translational modifications of RORα2 provides new avenues for the development of tumor-suppressive therapeutic agents through modulating the human isoform-specific tumorigenic role of RORα2. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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19 pages, 3546 KiB  
Article
Onconase Restores Cytotoxicity in Dabrafenib-Resistant A375 Human Melanoma Cells and Affects Cell Migration, Invasion and Colony Formation Capability
by Alice Raineri, Sabrina Fasoli, Rachele Campagnari, Giovanni Gotte and Marta Menegazzi
Int. J. Mol. Sci. 2019, 20(23), 5980; https://doi.org/10.3390/ijms20235980 - 27 Nov 2019
Cited by 14 | Viewed by 3780
Abstract
Melanoma is a lethal tumor because of its severe metastatic potential, and serine/threonine-protein kinase B-raf inhibitors (BRAFi) are used in patients harboring BRAF-mutation. Unfortunately, BRAFi induce resistance. Therefore, we tested the activity of onconase (ONC), a cytotoxic RNase variant, against BRAFi-resistant cells to [...] Read more.
Melanoma is a lethal tumor because of its severe metastatic potential, and serine/threonine-protein kinase B-raf inhibitors (BRAFi) are used in patients harboring BRAF-mutation. Unfortunately, BRAFi induce resistance. Therefore, we tested the activity of onconase (ONC), a cytotoxic RNase variant, against BRAFi-resistant cells to re-establish the efficacy of the chemotherapy. To do so, an A375 dabrafenib-resistant (A375DR) melanoma cell subpopulation was selected and its behavior compared with that of parental (A375P) cells by crystal violet, 5-Bromo-2’-deoxyuridine incorporation, and cleaved poly(ADP-ribose) polymerase 1 (PARP1) western blot measurements. Then, nuclear p65 Nuclear Factor kappaB (NF-κB) and IκB kinases-α/β (IKK) phosphorylation levels were measured. Gelatin zymography was performed to evaluate metalloproteinase 2 (MMP2) activity. In addition, assays to measure migration, invasion and soft agar colony formation were performed to examine the tumor cell dissemination propensity. ONC affected the total viability and the proliferation rate of both A375P and A375DR cell subpopulations in a dose-dependent manner and also induced apoptotic cell death. Among its pleiotropic effects, ONC reduced nuclear p65 NF-κB amount and IKK phosphorylation level, as well as MMP2 activity in both cell subpopulations. ONC decreased cell colony formation, migration, and invasion capability. Notably, it induced apoptosis and inhibited colony formation and invasiveness more extensively in A375DR than in A375P cells. In conclusion, ONC successfully counteracts melanoma malignancy especially in BRAFi-resistant cells and could become a tool against melanoma recurrence. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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14 pages, 2300 KiB  
Article
N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer
by Su Chan Park, Il-Geun Park, Hyunkyung Kim and Ji Min Lee
Int. J. Mol. Sci. 2019, 20(7), 1684; https://doi.org/10.3390/ijms20071684 - 4 Apr 2019
Cited by 17 | Viewed by 3405
Abstract
Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed [...] Read more.
Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from RORα-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in RORα-deficient embryonic fibroblasts, and reconstitution of RORα1 inhibited this activation by a NTD dependent manner. Downregulation of RORα1 and upregulation of Wnt/β-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated RORα1 signaling, suggesting advanced approaches for the development of therapeutic drugs. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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Review

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19 pages, 916 KiB  
Review
PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy
by Fabiana Conciatori, Chiara Bazzichetto, Italia Falcone, Ludovica Ciuffreda, Gianluigi Ferretti, Sabrina Vari, Virginia Ferraresi, Francesco Cognetti and Michele Milella
Int. J. Mol. Sci. 2020, 21(15), 5337; https://doi.org/10.3390/ijms21155337 - 27 Jul 2020
Cited by 29 | Viewed by 3563
Abstract
Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic [...] Read more.
Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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19 pages, 1024 KiB  
Review
Mitochondria Targeting as an Effective Strategy for Cancer Therapy
by Poorva Ghosh, Chantal Vidal, Sanchareeka Dey and Li Zhang
Int. J. Mol. Sci. 2020, 21(9), 3363; https://doi.org/10.3390/ijms21093363 - 9 May 2020
Cited by 167 | Viewed by 12044
Abstract
Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor [...] Read more.
Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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12 pages, 1330 KiB  
Review
Mathematical Modeling of p53 Pathways
by Eunjung Kim, Jae-Young Kim and Joo-Yong Lee
Int. J. Mol. Sci. 2019, 20(20), 5179; https://doi.org/10.3390/ijms20205179 - 18 Oct 2019
Cited by 14 | Viewed by 3986
Abstract
Cells have evolved balanced systems that ensure an appropriate response to stress. The systems elicit repair responses in temporary or moderate stress but eliminate irreparable cells via apoptosis in detrimental conditions of prolonged or severe stress. The tumor suppressor p53 is a central [...] Read more.
Cells have evolved balanced systems that ensure an appropriate response to stress. The systems elicit repair responses in temporary or moderate stress but eliminate irreparable cells via apoptosis in detrimental conditions of prolonged or severe stress. The tumor suppressor p53 is a central player in these stress response systems. When activated under DNA damage stress, p53 regulates hundreds of genes that are involved in DNA repair, cell cycle, and apoptosis. Recently, increasing studies have demonstrated additional regulatory roles of p53 in metabolism and mitochondrial physiology. Due to the inherent complexity of feedback loops between p53 and its target genes, the application of mathematical modeling has emerged as a novel approach to better understand the multifaceted functions and dynamics of p53. In this review, we discuss several mathematical modeling approaches in exploring the p53 pathways. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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34 pages, 2642 KiB  
Review
Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression
by Chloé Laplagne, Marcin Domagala, Augustin Le Naour, Christophe Quemerais, Dimitri Hamel, Jean-Jacques Fournié, Bettina Couderc, Corinne Bousquet, Audrey Ferrand and Mary Poupot
Int. J. Mol. Sci. 2019, 20(19), 4719; https://doi.org/10.3390/ijms20194719 - 23 Sep 2019
Cited by 53 | Viewed by 6998
Abstract
The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for [...] Read more.
The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules. Full article
(This article belongs to the Special Issue Tumour Suppressor Function)
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