Cancers

Research

Jump to: Review

17 pages, 3766 KiB

Open AccessArticle

BRG1 Activates Proliferation and Transcription of Cell Cycle-Dependent Genes in Breast Cancer Cells

by Maciej Sobczak, Julita Pietrzak, Tomasz Płoszaj and Agnieszka Robaszkiewicz

Cancers 2020, 12(2), 349; https://doi.org/10.3390/cancers12020349 - 4 Feb 2020

Cited by 21 | Viewed by 5151

Abstract

Cancer malignancy is usually characterized by unlimited self-renewal. In some types of advanced tumors that are rapidly dividing, gene expression profiles depict elevations in pro-proliferative genes accompanied by coordinately elevated transcription of factors responsible for removal of DNA lesions. In our studies, fast [...] Read more.

Cancer malignancy is usually characterized by unlimited self-renewal. In some types of advanced tumors that are rapidly dividing, gene expression profiles depict elevations in pro-proliferative genes accompanied by coordinately elevated transcription of factors responsible for removal of DNA lesions. In our studies, fast proliferating breast cancer cell lines (MDA-MB-231 and MCF7), BRG1, a component of the SWI/SNF complex, emerges as an activator of functionally-linked genes responsible for activities such as mitotic cell divisions and DNA repair. Products of at least some of them are considerably overrepresented in breast cancer cells and BRG1 facilitates growth of MCF7 and MDA-MB-231 cell lines. BRG1 occurs at the promoters of genes such as CDK4, LIG1, and NEIL3, which are transcriptionally controlled by cell cycle progression and highly acetylated by EP300 in proliferating cells. As previously documented, in dividing cells BRG1 directly activates gene transcription by evicting EP300 modified nucleosomes from the promoters and, thereby, relaxing chromatin. However, the deficiency of BRG1 or EP300 activity for 48 h leads to cell growth arrest and to chromatin compaction, but also to the assembly of RB1/HDAC1/EZH2 complexes at the studied cell cycle-dependent gene promoters. Epigenetic changes include histone deacetylation and accumulation of H3K27me trimethylation, both known to repress transcription. Cell cycle arrest in G1 by inhibition of CDK4/6 phenocopies the effect of the long-term BRG1 inhibition on the chromatin structure. These results suggest that BRG1 may control gene transcription also by promoting expression of genes responsible for cell cycle progression in the studied breast cancer cells. In the current study, we show that BRG1 binding occurs at the promoters of functionally linked genes in proliferating breast cancer cells, revealing a new mechanism by which BRG1 defines gene transcription. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

15 pages, 3484 KiB

Open AccessArticle

MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells

by Mei-Chuan Chen, Yu-Chen Lin, Yu-Hsuan Liao, Jing-Ping Liou and Chun-Han Chen

Cancers 2019, 11(10), 1617; https://doi.org/10.3390/cancers11101617 - 22 Oct 2019

Cited by 31 | Viewed by 4494

Abstract

Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective [...] Read more.

Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor activity against several solid tumors. The purpose of the present study was to evaluate the feasibility and pharmacological mechanisms of MPT0G612 as a potential therapy for CRC patients. Results revealed that MPT0G612 significantly suppresses the proliferation and viability, as well as induces apoptosis in CRC cells. Autophagy activation with LC3B-II formation and p62 degradation was observed, and the inhibition of autophagy by pharmacological inhibitor or Atg5 knockdown enhances MPT0G612-induced cell death. In addition, HDAC6 knockdown reduces MPT0G612-mediated autophagy and further potentiates apoptotic cell death. Furthermore, MPT0G612 downregulates the expression of PD-L1 induced by IFN-γ in CRC cells. These results suggest that MPT0G612 is a potent cell death inducer through inhibiting HDAC6-associated pathway, and a potential agent for combination strategy with immune checkpoint inhibitors for the treatment of CRC. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

24 pages, 2490 KiB

Open AccessArticle

The Histone Demethylase LSD1/ΚDM1A Mediates Chemoresistance in Breast Cancer via Regulation of a Stem Cell Program

by John Verigos, Panagiotis Karakaidos, Dimitris Kordias, Alexandra Papoudou-Bai, Zoi Evangelou, Haralampos V. Harissis, Apostolos Klinakis and Angeliki Magklara

Cancers 2019, 11(10), 1585; https://doi.org/10.3390/cancers11101585 - 17 Oct 2019

Cited by 54 | Viewed by 5708

Abstract

Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug [...] Read more.

Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Cancer stem cells (CSCs) are a small subset of tumor cells characterized by self-renewal, increased tumor-initiation capacity, and resistance to conventional therapies. As such, they have been implicated in the etiology of tumor recurrence and have emerged as promising targets for the development of novel therapies. Here, we show that the histone demethylase lysine-specific demethylase 1 (LSD1) plays an important role in the chemoresistance of breast cancer cells. Our data, from a series of in vitro and in vivo assays, advocate for LSD1 being critical in maintaining a pool of tumor-initiating cells that may contribute to the development of drug resistance. Combinatory administration of LSD1 inhibitors and anti-cancer drugs is more efficacious than monotherapy alone in eliminating all tumor cells in a 3D spheroid system. In conclusion, we provide compelling evidence that LSD1 is a key regulator of breast cancer stemness and a potential target for the design of future combination therapies. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

26 pages, 7994 KiB

Open AccessArticle

HMGA1 Modulates Gene Transcription Sustaining a Tumor Signalling Pathway Acting on the Epigenetic Status of Triple-Negative Breast Cancer Cells

by Carlotta Penzo, Laura Arnoldo, Silvia Pegoraro, Sara Petrosino, Gloria Ros, Rossella Zanin, Jacek R. Wiśniewski, Guidalberto Manfioletti and Riccardo Sgarra

Cancers 2019, 11(8), 1105; https://doi.org/10.3390/cancers11081105 - 2 Aug 2019

Cited by 15 | Viewed by 5297

Abstract

Chromatin accessibility plays a critical factor in regulating gene expression in cancer cells. Several factors, including the High Mobility Group A (HMGA) family members, are known to participate directly in chromatin relaxation and transcriptional activation. The HMGA1 oncogene encodes an architectural chromatin transcription [...] Read more.

Chromatin accessibility plays a critical factor in regulating gene expression in cancer cells. Several factors, including the High Mobility Group A (HMGA) family members, are known to participate directly in chromatin relaxation and transcriptional activation. The HMGA1 oncogene encodes an architectural chromatin transcription factor that alters DNA structure and interacts with transcription factors favouring their landing onto transcription regulatory sequences. Here, we provide evidence of an additional mechanism exploited by HMGA1 to modulate transcription. We demonstrate that, in a triple-negative breast cancer cellular model, HMGA1 sustains the action of epigenetic modifiers and in particular it positively influences both histone H3S10 phosphorylation by ribosomal protein S6 kinase alpha-3 (RSK2) and histone H2BK5 acetylation by CREB-binding protein (CBP). HMGA1, RSK2, and CBP control the expression of a set of genes involved in tumor progression and epithelial to mesenchymal transition. These results suggest that HMGA1 has an effect on the epigenetic status of cancer cells and that it could be exploited as a responsiveness predictor for epigenetic therapies in triple-negative breast cancers. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Graphical abstract

15 pages, 1686 KiB

Open AccessArticle

Genes Located on 18q23 Are Epigenetic Markers and Have Prognostic Significance for Patients with Head and Neck Cancer

by Kiyoshi Misawa, Takeharu Kanazawa, Daiki Mochizuki, Atsushi Imai, Masato Mima, Satoshi Yamada, Kotaro Morita, Yuki Misawa, Kazuya Shinmura and Hiroyuki Mineta

Cancers 2019, 11(3), 401; https://doi.org/10.3390/cancers11030401 - 21 Mar 2019

Cited by 5 | Viewed by 3236

Abstract

Loss of heterozygosity (LOH) on chromosome 18q23 is associated with significantly decreased survival in head and neck cancer. In agreement with such tumor suppressive roles, the loss of function of genes located in this region can be achieved through LOH and promotor hypermethylation. [...] Read more.

Loss of heterozygosity (LOH) on chromosome 18q23 is associated with significantly decreased survival in head and neck cancer. In agreement with such tumor suppressive roles, the loss of function of genes located in this region can be achieved through LOH and promotor hypermethylation. In this study, the methylation status of promoters of 18q23 genes in 243 head and neck cancer patients was assessed by quantitative methylation-specific PCR. Promoter methylation was then compared to various clinical characteristics and patient survival. GALR1 and SALL3 promoter methylation correlated with reduced disease-free survival (log-rank test, p = 0.018 and p = 0.013, respectively). Furthermore, based on multivariate Cox proportional hazards analysis, these methylation events were associated with poor disease-free survival, with hazard ratios of 1.600 (95% confidence interval: CI, 1.027–2.493; p = 0.038) and 1.911 (95% CI, 1.155–3.162; p = 0.012), respectively. By comparison, GALR1 and SALL3 methylation were not prognostic for overall survival in The Cancer Genome Atlas (TCGA) cohort. Our findings suggest that the methylation status of 18q23 genes could serve as important biomarkers for the prediction of clinical outcomes in well-annotated head and neck squamous cell carcinoma cohorts. GALR1 and SALL3 methylation could thus help to facilitate risk stratification for individualized treatment. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

Review

Jump to: Research

30 pages, 3913 KiB

Open AccessReview

Epigenetic Deregulation of Apoptosis in Cancers

by Ezgi Ozyerli-Goknar and Tugba Bagci-Onder

Cancers 2021, 13(13), 3210; https://doi.org/10.3390/cancers13133210 - 27 Jun 2021

Cited by 41 | Viewed by 4269

Abstract

Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression [...] Read more.

Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

18 pages, 816 KiB

Open AccessReview

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

by Cinzia Bottino, Alessia Peserico, Cristiano Simone and Giuseppina Caretti

Cancers 2020, 12(1), 142; https://doi.org/10.3390/cancers12010142 - 6 Jan 2020

Cited by 48 | Viewed by 5667

Abstract

SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. [...] Read more.

SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

20 pages, 1287 KiB

Open AccessReview

Immunological Effects of Epigenetic Modifiers

by Lucillia Bezu, Alejandra Wu Chuang, Peng Liu, Guido Kroemer and Oliver Kepp

Cancers 2019, 11(12), 1911; https://doi.org/10.3390/cancers11121911 - 1 Dec 2019

Cited by 16 | Viewed by 4480

Abstract

Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as [...] Read more.

Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

36 pages, 1777 KiB

Open AccessReview

The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer

by Nesrin Hasan and Nita Ahuja

Cancers 2019, 11(12), 1859; https://doi.org/10.3390/cancers11121859 - 25 Nov 2019

Cited by 24 | Viewed by 7565

Abstract

Pancreatic cancer is an aggressive cancer with low survival rates. Genetic and epigenetic dysregulation has been associated with the initiation and progression of pancreatic tumors. Multiple studies have pointed to the involvement of aberrant chromatin modifications in driving tumor behavior. ATP-dependent chromatin remodeling [...] Read more.

Pancreatic cancer is an aggressive cancer with low survival rates. Genetic and epigenetic dysregulation has been associated with the initiation and progression of pancreatic tumors. Multiple studies have pointed to the involvement of aberrant chromatin modifications in driving tumor behavior. ATP-dependent chromatin remodeling complexes regulate chromatin structure and have critical roles in stem cell maintenance, development, and cancer. Frequent mutations and chromosomal aberrations in the genes associated with subunits of the ATP-dependent chromatin remodeling complexes have been detected in different cancer types. In this review, we summarize the current literature on the genomic alterations and mechanistic studies of the ATP-dependent chromatin remodeling complexes in pancreatic cancer. Our review is focused on the four main subfamilies: SWItch/sucrose non-fermentable (SWI/SNF), imitation SWI (ISWI), chromodomain-helicase DNA-binding protein (CHD), and INOsitol-requiring mutant 80 (INO80). Finally, we discuss potential novel treatment options that use small molecules to target these complexes. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

21 pages, 2262 KiB

Open AccessReview

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

by Panagiotis Karakaidos, John Verigos and Angeliki Magklara

Cancers 2019, 11(12), 1821; https://doi.org/10.3390/cancers11121821 - 20 Nov 2019

Cited by 79 | Viewed by 9511

Abstract

A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming [...] Read more.

A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

24 pages, 956 KiB

Open AccessReview

HDAC Inhibitors in Acute Myeloid Leukemia

by Edurne San José-Enériz, Naroa Gimenez-Camino, Xabier Agirre and Felipe Prosper

Cancers 2019, 11(11), 1794; https://doi.org/10.3390/cancers11111794 - 14 Nov 2019

Cited by 124 | Viewed by 13094

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic [...] Read more.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

17 pages, 691 KiB

Open AccessReview

Epigenetic Reprogramming for Targeting IDH-Mutant Malignant Gliomas

by Jong-Whi Park and Şevin Turcan

Cancers 2019, 11(10), 1616; https://doi.org/10.3390/cancers11101616 - 22 Oct 2019

Cited by 18 | Viewed by 8585

Abstract

Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit [...] Read more.

Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

22 pages, 4094 KiB

Open AccessReview

Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors

by Pierre Autin, Christophe Blanquart and Delphine Fradin

Cancers 2019, 11(10), 1530; https://doi.org/10.3390/cancers11101530 - 10 Oct 2019

Cited by 42 | Viewed by 5891

Abstract

Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. [...] Read more.

Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

21 pages, 46064 KiB

Open AccessReview

LncRNAs as Chromatin Regulators in Cancer: From Molecular Function to Clinical Potential

by Rodiola Begolli, Nikos Sideris and Antonis Giakountis

Cancers 2019, 11(10), 1524; https://doi.org/10.3390/cancers11101524 - 10 Oct 2019

Cited by 64 | Viewed by 4857

Abstract

During the last decade, high-throughput sequencing efforts in the fields of transcriptomics and epigenomics have shed light on the noncoding part of the transcriptome and its potential role in human disease. Regulatory noncoding RNAs are broadly divided into short and long noncoding transcripts. [...] Read more.

During the last decade, high-throughput sequencing efforts in the fields of transcriptomics and epigenomics have shed light on the noncoding part of the transcriptome and its potential role in human disease. Regulatory noncoding RNAs are broadly divided into short and long noncoding transcripts. The latter, also known as lncRNAs, are defined as transcripts longer than 200 nucleotides with low or no protein-coding potential. LncRNAs form a diverse group of transcripts that regulate vital cellular functions through interactions with proteins, chromatin, and even RNA itself. Notably, an important regulatory aspect of these RNA species is their association with the epigenetic machinery and the recruitment of its regulatory apparatus to specific loci, resulting in DNA methylation and/or post-translational modifications of histones. Such epigenetic modifications play a pivotal role in maintaining the active or inactive transcriptional state of chromatin and are crucial regulators of normal cellular development and tissue-specific gene expression. Evidently, aberrant expression of lncRNAs that interact with epigenetic modifiers can cause severe epigenetic disruption and is thus is closely associated with altered gene function, cellular dysregulation, and malignant transformation. Here, we survey the latest breakthroughs concerning the role of lncRNAs interacting with the epigenetic machinery in various forms of cancer. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

20 pages, 1190 KiB

Open AccessReview

Gene-Specific Targeting of DNA Methylation in the Mammalian Genome

by Arthur Urbano, Jim Smith, Robert J. Weeks and Aniruddha Chatterjee

Cancers 2019, 11(10), 1515; https://doi.org/10.3390/cancers11101515 - 9 Oct 2019

Cited by 48 | Viewed by 7199

Abstract

DNA methylation is the most widely-studied epigenetic modification, playing a critical role in the regulation of gene expression. Dysregulation of DNA methylation is implicated in the pathogenesis of numerous diseases. For example, aberrant DNA methylation in promoter regions of tumor-suppressor genes has been [...] Read more.

DNA methylation is the most widely-studied epigenetic modification, playing a critical role in the regulation of gene expression. Dysregulation of DNA methylation is implicated in the pathogenesis of numerous diseases. For example, aberrant DNA methylation in promoter regions of tumor-suppressor genes has been strongly associated with the development and progression of many different tumors. Accordingly, technologies designed to manipulate DNA methylation at specific genomic loci are very important, especially in the context of cancer therapy. Traditionally, epigenomic editing technologies have centered around zinc finger proteins (ZFP)- and transcription activator-like effector protein (TALE)-based targeting. More recently, however, the emergence of clustered regulatory interspaced short palindromic repeats (CRISPR)-deactivated Cas9 (dCas9)-based editing systems have shown to be a more specific and efficient method for the targeted manipulation of DNA methylation. Here, we describe the regulation of the DNA methylome, its significance in cancer and the current state of locus-specific editing technologies for altering DNA methylation. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Graphical abstract

14 pages, 1214 KiB

Open AccessReview

DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?

by Raquel Ordoñez, Nicolás Martínez-Calle, Xabier Agirre and Felipe Prosper

Cancers 2019, 11(10), 1424; https://doi.org/10.3390/cancers11101424 - 24 Sep 2019

Cited by 18 | Viewed by 6713 | Correction

Abstract

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. [...] Read more.

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

17 pages, 1023 KiB

Open AccessReview

Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer

by Sudha Suriyamurthy, David Baker, Peter ten Dijke and Prasanna Vasudevan Iyengar

Cancers 2019, 11(5), 726; https://doi.org/10.3390/cancers11050726 - 24 May 2019

Cited by 55 | Viewed by 9695

Abstract

The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor [...] Read more.

The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

16 pages, 833 KiB

Open AccessReview

Macro Histone Variants: Emerging Rheostats of Gastrointestinal Cancers

by Sebastiano Giallongo, Oriana Lo Re and Manlio Vinciguerra

Cancers 2019, 11(5), 676; https://doi.org/10.3390/cancers11050676 - 15 May 2019

Cited by 17 | Viewed by 4256

Abstract

Gastrointestinal cancers (GC) are malignancies involving the gastrointestinal (GI) tract and accessory organs of the digestive system, including the pancreas, liver, and gall bladder. GC is one of the most common cancers and contributes to more cancer-related deaths than cancers of any other [...] Read more.

Gastrointestinal cancers (GC) are malignancies involving the gastrointestinal (GI) tract and accessory organs of the digestive system, including the pancreas, liver, and gall bladder. GC is one of the most common cancers and contributes to more cancer-related deaths than cancers of any other system in the human body. Causative factors of GC have been consistently attributed to infections, smoking, an unhealthy diet, obesity, diabetes, and genetic factors. More recently, aberrant epigenetic regulation of gene expression has emerged as a new, fundamental pathway in GC pathogenesis. In this review, we summarize the role of the macroH2A histone family in GI cell function and malignant transformation, and highlight how this histone family may open up novel biomarkers for cancer detection, prediction, and response to treatment. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

22 pages, 2908 KiB

Open AccessReview

microRNA-23a in Human Cancer: Its Roles, Mechanisms and Therapeutic Relevance

by Ning Wang, Hor-Yue Tan, Yi-Gang Feng, Cheng Zhang, Feiyu Chen and Yibin Feng

Cancers 2019, 11(1), 7; https://doi.org/10.3390/cancers11010007 - 20 Dec 2018

Cited by 70 | Viewed by 6882

Abstract

microRNA-23a (miR-23a) is one of the most extensively studied miRNAs in different types of human cancer, and plays various roles in the initiation, progression, and treatment of tumors. Here, we comprehensively summarize and discuss the recent findings about the role of miR-23a in [...] Read more.

microRNA-23a (miR-23a) is one of the most extensively studied miRNAs in different types of human cancer, and plays various roles in the initiation, progression, and treatment of tumors. Here, we comprehensively summarize and discuss the recent findings about the role of miR-23a in cancer. The differential expression of tissue miR-23a was reported, potentially indicating cancer stages, angiogenesis, and metastasis. miR-23a in human biofluid, such as plasma and salivary fluid, may be a sensitive and specific marker for early diagnosis of cancer. Tissue and circulating miR-23a serves as a prognostic factor for cancer patient survival, as well as a predictive factor for response to anti-tumor treatment. The direct and indirect regulation of miR-23a on multiple gene expression and signaling transduction mediates carcinogenesis, tumor proliferation, survival, cell migration and invasion, as well as the response to anti-tumor treatment. Tumor cell-derived miR-23a regulates the microenvironment of human cancer through manipulating both immune function and tumor vascular development. Several transcriptional and epigenetic factors may contribute to the dysregulation of miR-23a in cancer. This evidence highlights the essential role of miR-23a in the application of cancer diagnosis, prognosis, and treatment. Full article

(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Epigenetic Dysregulation in Cancer: From Mechanism to Therapy

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (19 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI