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At the Interface of Genetics, Epigenetics and Metabolism in Cancer

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

Deadline for manuscript submissions: closed (17 January 2023) | Viewed by 32602

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Special Issue Editors

Dr. Kenta Masui

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Guest Editor

Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan
Interests: cancer metabolism; epigenetics; mTOR complex; glioblastoma; molecular pathology

Dr. Linlin Guo

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Guest Editor

Department of Obstetrics and Gynaecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
Interests: cancer; therapy; signaling pathway; HER; EGF; Wnt; notch; TGF-β; mTOR; PD-1/PD-L1
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advancement in comprehending cancer genomics has culminated in a cancer diagnostic scheme classified by tissue and cell type of origin and, more importantly, by its molecular-genetic composition. The molecular aspect of cancer classification is based primarily on oncogene gains, tumor suppressor losses, and associated transcriptomic shift. However, the phenotypes of cancer cells are represented more by profound alterations in cellular metabolism and epigenetic landscape, and it is of particular importance that oncogenic genomic aberration enables tumor cells to maximize their survival and drug resistance by taking advantage of dynamic flow of nutrients in systemic microenvironments. Furthermore, changes in nutrient uptake and utilization directly affect chromatin structure, which is central to this dynamic behavior. This Special Issue will highlight a set of recent discoveries on metabolic and epigenetic reprogramming in cancer; in particular, it will focus on the “co-dependency” of genetics, epigenetics and metabolism, which contributes to the aggressive phenotypes of cancer cells, suggesting that these aberrations do not constitute a one-way street to sustaining cancer cell survival on their own, but that the mutual interdependency of genetics, epigenetics and metabolism could be a key to facilitating tumor progression, which will be, at the same time, an Achilles’ heel. These underscore the integration of genetic mutations with metabolic and epigenetic reprogramming in cancer, suggesting a new means to identifying patient subsets suitable for specific precision therapeutics.

Dr. Kenta Masui
Dr. Linlin Guo
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

cancer metabolism
epigenetic reprogramming
histone modification
DNA methylation
chromatin structure
intermediary metabolites
microenvironment
mTOR complexes
glioblastoma

Published Papers (11 papers)

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Research

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17 pages, 3656 KiB

Open AccessArticle

Regulation of Chromatin Accessibility by the Farnesoid X Receptor Is Essential for Circadian and Bile Acid Homeostasis In Vivo

by Haider M. Hassan, Oladapo Onabote, Majdina Isovic, Daniel T. Passos, Frederick A. Dick and Joseph Torchia

Cancers 2022, 14(24), 6191; https://doi.org/10.3390/cancers14246191 - 15 Dec 2022

Cited by 3 | Viewed by 1691

Abstract

The Farnesoid X Receptor (FXR) belongs to the nuclear receptor superfamily and is an essential bile acid (BA) receptor that regulates the expression of genes involved in the metabolism of BAs. FXR protects the liver from BA overload, which is a major etiology of hepatocellular carcinoma. Herein, we investigated the changes in gene expression and chromatin accessibility in hepatocytes by performing RNA-seq in combination with the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) using a novel FXR knockout mouse model (Fxr^ex5Δ: Nr1h4^ex5Δ/ex5Δ) generated through CRISPR/Cas9. Consistent with previous Fxr knockout models, we found that Fxr^ex5Δ mice develop late-onset HCC associated with increased serum and hepatic BAs. FXR deletion was associated with a dramatic loss of chromatin accessibility, primarily at promoter-associated transcription factor binding sites. Importantly, several genes involved in BA biosynthesis and circadian rhythm were downregulated following loss of FXR, also displayed reduced chromatin accessibility at their promoter regions. Altogether, these findings suggest that FXR helps to maintain a transcriptionally active state by regulating chromatin accessibility through its binding and recruitment of transcription factors and coactivators. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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20 pages, 3551 KiB

Open AccessArticle

Utilizing an Endogenous Progesterone Receptor Reporter Gene for Drug Screening and Mechanistic Study in Endometrial Cancer

by Yiyang Li, Wei Zhou, Xiangbing Meng, Sarina D. Murray, Long Li, Abby Fronk, Vanessa J. Lazaro-Camp, Kuo-kuang Wen, Meng Wu, Adam Dupuy, Kimberly K. Leslie and Shujie Yang

Cancers 2022, 14(19), 4883; https://doi.org/10.3390/cancers14194883 - 6 Oct 2022

Cited by 1 | Viewed by 1719

Abstract

Expression of progesterone receptor (PR) is a favorable prognostic marker for multiple solid tumors. However, PR expression is reduced or lost in malignant tumors. Thus, monitoring and restoring functional PR expression is important in order to sensitize tumor cells to progesterone therapy in endometrial cancer. We developed stable PR reporter gene containing endometrial cancer cell lines monitoring the endogenous PR expression by inserting mCherry and hygromycin resistant gene at the endogenous PR gene locus by CRISPR/Cas9-mediated genome editing technique. This allows efficient, real-time monitoring of PR expression in its native epigenetic landscape. Reporter gene expression faithfully reflects and amplifies PR expression following treatment with drugs known to induce PR expression. Small molecular PR inducers have been identified from the FDA-approved 1018 drug library and tested for their ability to restore PR expression. Additionally, several candidate PR repressors have been identified by screening the genome-wide CRISPR knockout (GeCKO) library. This novel endogenous PR reporter gene system facilitates the discovery of a new treatment strategy to enhance PR expression and further sensitize progestin therapy in endometrial cancer. These tools provide a systematic, unbiased approach for monitoring target gene expression, allowing for novel drug discovery and mechanistic exploration. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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Review

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35 pages, 2273 KiB

Open AccessReview

Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer

by Brittany P. Rickard, Marta Overchuk, Vesna A. Chappell, Mustafa Kemal Ruhi, Prima Dewi Sinawang, Tina Thuy Nguyen Hoang, Demir Akin, Utkan Demirci, Walfre Franco, Suzanne E. Fenton, Janine H. Santos and Imran Rizvi

Cancers 2023, 15(9), 2564; https://doi.org/10.3390/cancers15092564 - 29 Apr 2023

Cited by 5 | Viewed by 2842

Abstract

Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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27 pages, 1339 KiB

Open AccessReview

Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform

by David A. Bunsick, Jenna Matsukubo and Myron R. Szewczuk

Cancers 2023, 15(4), 1030; https://doi.org/10.3390/cancers15041030 - 6 Feb 2023

Cited by 1 | Viewed by 2864

Abstract

The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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20 pages, 809 KiB

Open AccessReview

Bone Metabolism Effects of Medical Therapy in Advanced Renal Cell Carcinoma

by Rosa Maria Paragliola, Francesco Torino, Agnese Barnabei, Giovanni Maria Iannantuono, Andrea Corsello, Pietro Locantore and Salvatore Maria Corsello

Cancers 2023, 15(2), 529; https://doi.org/10.3390/cancers15020529 - 15 Jan 2023

Cited by 3 | Viewed by 2823

Abstract

The medical therapy of advanced renal cell carcinoma (RCC) is based on the use of targeted therapies, such as tyrosine kinase inhibitors (TKI) and immune-checkpoint inhibitors (ICI). These therapies are characterized by multiple endocrine adverse events, but the effect on the bone is still less known. Relatively few case reports or small case series have been specifically focused on TKI and ICI effects on bone metabolism. However, the importance to consider these possible side effects is easily intuitable because the bone is one of the most frequent metastatic sites of RCC. Among TKI used in RCC, sunitinib and sorafenib can cause hypophosphatemia with increased PTH levels and low-normal serum calcium levels. Considering ICI, nivolumab and ipilimumab, which can be used in association in a combination strategy, are associated with an increased risk of hypocalcemia, mediated by an autoimmune mechanism targeted on the calcium-sensing receptor. A fearsome complication, reported for TKI and rarely for ICI, is osteonecrosis of the jaw. Awareness of these possible side effects makes a clinical evaluation of RCC patients on anticancer therapy mandatory, especially if associated with antiresorptive therapy such as bisphosphonates and denosumab, which can further increase the risk of these complications. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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19 pages, 798 KiB

Open AccessReview

Endosomal Sorting Protein SNX27 and Its Emerging Roles in Human Cancers

by Shreya Deb and Jun Sun

Cancers 2023, 15(1), 70; https://doi.org/10.3390/cancers15010070 - 22 Dec 2022

Cited by 1 | Viewed by 2337

Abstract

SNX27 belongs to the sorting nexin (SNX) family of proteins that play a critical role in protein sorting and trafficking in the endocytosis pathway. This protein family is characterized by the presence of a Phox (PX) domain; however, SNX27 is unique in containing an additional PDZ domain. Recently, SNX27 has gained popularity as an important sorting protein that is associated with the retromer complex and mediates the recycling of internalized proteins from endosomes to the plasma membrane in a PDZ domain-dependent manner. Over 100 cell surface proteins have been identified as binding partners of the SNX27–retromer complex. However, the roles and underlying mechanisms governed by SNX27 in tumorigenesis remains to be poorly understood. Many of its known binding partners include several G-protein coupled receptors, such as β2-andrenergic receptor and parathyroid hormone receptor, are associated with multiple pathways implicated in oncogenic signaling and tumorigenesis. Additionally, SNX27 mediates the recycling of GLUT1 and the activation of mTORC1, both of which can regulate intracellular energy balance and promote cell survival and proliferation under conditions of nutrient deprivation. In this review, we summarize the structure and fundamental roles of SNX proteins, with a focus on SNX27, and provide the current evidence indicating towards the role of SNX27 in human cancers. We also discuss the gap in the field and future direction of SNX27 research. Insights into the emerging roles and mechanism of SNX27 in cancers will provide better development strategies to prevent and treat tumorigenesis. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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16 pages, 1873 KiB

Open AccessReview

Factors and Mechanisms That Influence Chromatin-Mediated Enhancer–Promoter Interactions and Transcriptional Regulation

by Shinsuke Ito, Nando Dulal Das, Takashi Umehara and Haruhiko Koseki

Cancers 2022, 14(21), 5404; https://doi.org/10.3390/cancers14215404 - 2 Nov 2022

Cited by 4 | Viewed by 4957

Abstract

Eukaryotic gene expression is regulated through chromatin conformation, in which enhancers and promoters physically interact (E–P interactions). How such chromatin-mediated E–P interactions affect gene expression is not yet fully understood, but the roles of histone acetylation and methylation, pioneer transcription factors, and architectural proteins such as CCCTC binding factor (CTCF) and cohesin have recently attracted attention. Moreover, accumulated data suggest that E–P interactions are mechanistically involved in biophysical events, including liquid–liquid phase separation, and in biological events, including cancers. In this review, we discuss various mechanisms that regulate eukaryotic gene expression, focusing on emerging views regarding chromatin conformations that are involved in E–P interactions and factors that establish and maintain them. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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16 pages, 1504 KiB

Open AccessReview

The Biological and Clinical Consequences of RNA Splicing Factor U2AF1 Mutation in Myeloid Malignancies

by Yangjing Zhao, Weili Cai, Ye Hua, Xiaochen Yang and Jingdong Zhou

Cancers 2022, 14(18), 4406; https://doi.org/10.3390/cancers14184406 - 10 Sep 2022

Cited by 12 | Viewed by 4294

Abstract

Mutations of spliceosome genes have been frequently identified in myeloid malignancies with the large-scale application of advanced sequencing technology. U2 small nuclear RNA auxiliary factor 1 (U2AF1), an essential component of U2AF heterodimer, plays a pivotal role in the pre-mRNA splicing processes to generate functional mRNAs. Over the past few decades, the mutation landscape of U2AF1 (most frequently involved S34 and Q157 hotspots) has been drawn in multiple cancers, particularly in myeloid malignancies. As a recognized early driver of myelodysplastic syndromes (MDSs), U2AF1 mutates most frequently in MDS, followed by acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). Here, for the first time, we summarize the research progress of U2AF1 mutations in myeloid malignancies, including the correlations between U2AF1 mutations with clinical and genetic characteristics, prognosis, and the leukemic transformation of patients. We also summarize the adverse effects of U2AF1 mutations on hematopoietic function, and the alterations in downstream alternative gene splicing and biological pathways, thus providing comprehensive insights into the roles of U2AF1 mutations in the myeloid malignancy pathogenesis. U2AF1 mutations are expected to be potential novel molecular markers for myeloid malignancies, especially for risk stratification, prognosis assessment, and a therapeutic target of MDS patients. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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13 pages, 309 KiB

Open AccessReview

New Genetic Technologies in Diagnosis and Treatment of Cancer of Unknown Primary

by Paweł Krawczyk, Jacek Jassem, Kamila Wojas-Krawczyk, Maciej Krzakowski, Rafał Dziadziuszko and Włodzimierz Olszewski

Cancers 2022, 14(14), 3429; https://doi.org/10.3390/cancers14143429 - 14 Jul 2022

Cited by 4 | Viewed by 1698

Abstract

Cancer of unknown primary (CUP) represents a rare oncological and heterogeneous disease in which one or more metastases are present, but the location of the primary site is unknown. Pathological diagnosis, using immunohistochemistry, of such metastatic materials is challenging and frequently does not allow for determining the tissue of origin (ToO). The selection of systemic therapy in patients with CUP is usually based on empiric grounds, and the prognosis is generally unfavourable. New molecular techniques could identify the tissue of origin and be used to select systemic agnostic therapies in various malignancies with specific molecular abnormalities. Targetable driver mutations or gene rearrangements in cancer cells may be identified using various molecular assays, of which particularly valuable are next-generation sequencing techniques. These assays may identify tumour sources and allow personalized treatments. However, current guidelines for CUP management do not recommend routine testing of gene expression and epigenetic factors. This is mainly due to the insufficient evidence supporting the improvement of CUP’s prognosis by virtue of this approach. This review summarizes the advantages and disadvantages of new genetic techniques in CUP diagnostics and proposes updating the recommendations for CUP management. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

18 pages, 1379 KiB

Open AccessReview

Glutathione Peroxidase GPX1 and Its Dichotomous Roles in Cancer

by Yangjing Zhao, Hui Wang, Jingdong Zhou and Qixiang Shao

Cancers 2022, 14(10), 2560; https://doi.org/10.3390/cancers14102560 - 23 May 2022

Cited by 35 | Viewed by 3875

Abstract

As the first identified selenoprotein, glutathione peroxidase 1 (GPX1) is a widely and abundantly expressed antioxidant enzyme. GPX1 utilizes glutathione as a substrate to catalyze hydrogen peroxide, lipid peroxide, and peroxynitrite, thereby reducing intracellular oxidative stress. The GPX1 gene is regulated at transcriptional, post-transcriptional, and translational levels. Numerous case-control studies and meta-analyses have assessed the association between a functional genetic polymorphism of the GPX1 gene, named Pro198Leu (rs1050450 C>T), and cancer susceptibility in different populations. GPX1 polymorphism has type-specific effects as a candidate marker for cancer risk, but the association between GPX1 variants and cancer susceptibility remains controversial in different studies. GPX1 is abnormally elevated in most types of cancer but has complex dichotomous roles as tumor suppressor and promoter in different cancers. GPX1 can participate in various signaling pathways to regulate tumor biological behaviors, including cell proliferation, apoptosis, invasion, immune response, and chemoresistance. In this review, we comprehensively summarize the controversial associations between GPX1 polymorphism and cancer risks and further discuss the relationships between the aberrant expressions of GPX1 and tumorigenesis. Further studies are needed to elucidate the clinical significance of GPX1 as a potential prognostic biomarker and novel therapeutic target in various malignancies. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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12 pages, 1260 KiB

Open AccessReview

Dysregulated TET Family Genes and Aberrant 5mC Oxidation in Breast Cancer: Causes and Consequences

by Bo Xu, Hao Wang and Li Tan

Cancers 2021, 13(23), 6039; https://doi.org/10.3390/cancers13236039 - 30 Nov 2021

Cited by 8 | Viewed by 2144

Abstract

DNA methylation (5-methylcytosine, 5mC) was once viewed as a stable epigenetic modification until Rao and colleagues identified Ten-eleven translocation 1 (TET1) as the first 5mC dioxygenase in 2009. TET family genes (including TET1, TET2, and TET3) encode proteins that can catalyze 5mC oxidation and consequently modulate DNA methylation, not only regulating embryonic development and cellular differentiation, but also playing critical roles in various physiological and pathophysiological processes. Soon after the discovery of TET family 5mC dioxygenases, aberrant 5mC oxidation and dysregulation of TET family genes have been reported in breast cancer as well as other malignancies. The impacts of aberrant 5mC oxidation and dysregulated TET family genes on the different aspects (so-called cancer hallmarks) of breast cancer have also been extensively investigated in the past decade. In this review, we summarize current understanding of the causes and consequences of aberrant 5mC oxidation in the pathogenesis of breast cancer. The challenges and future perspectives of this field are also discussed. Full article

(This article belongs to the Special Issue At the Interface of Genetics, Epigenetics and Metabolism in Cancer)

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