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Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways
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Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways

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

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 81796

Special Issue Editor

Prof. Dr. Daniele Filippo Condorelli

E-Mail Website
Guest Editor
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Interests: gene regulation; mRNA; transcriptomic analysis; cancer genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The recent suggestion of anticancer therapies based on tools that selectively modify transcriptional activity promotes the identification of potential transcriptional targets. Indeed, both coding and non-coding transcripts are involved in cancer transcriptional dysregulation and alterations of RNA modification processes and networks of interacting non-coding RNAs can impinge on the post-transcriptional regulation of mRNAs. While much attention has been dedicated to linking point-mutations and gene-fusions to cancer driver pathway dysfunctions, less effort has been devoted to genomic aberrations leading to transcriptional and post-transcriptional alterations. Therefore, the description of cancer transcriptional and post-transcriptional dysregulation and its impact on cancer driver pathways represents one of the crucial issues of molecular cancer research.

Prof. Dr. Daniele Filippo Condorelli
Guest Editor

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Keywords

  • cancer
  • transcriptomics
  • genomics
  • cancer driver genes
  • somatic copy number aberrations
  • long non-coding RNA
  • miRNA
  • mRNA
  • RNA splicing
  • RNA editing

Published Papers (17 papers)

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Research

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13 pages, 1934 KiB  
Article
Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion
by Tomas Zikmund, Helena Paszekova, Juraj Kokavec, Paul Kerbs, Shefali Thakur, Tereza Turkova, Petra Tauchmanova, Philipp A. Greif and Tomas Stopka
Int. J. Mol. Sci. 2020, 21(6), 2073; https://doi.org/10.3390/ijms21062073 - 18 Mar 2020
Cited by 16 | Viewed by 3594
Abstract
ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute [...] Read more.
ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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19 pages, 3443 KiB  
Article
Chromosomal Density of Cancer Up-Regulated Genes, Aberrant Enhancer Activity and Cancer Fitness Genes Are Associated with Transcriptional Cis-Effects of Broad Copy Number Gains in Colorectal Cancer
by Daniele Filippo Condorelli, Anna Provvidenza Privitera and Vincenza Barresi
Int. J. Mol. Sci. 2019, 20(18), 4652; https://doi.org/10.3390/ijms20184652 - 19 Sep 2019
Cited by 13 | Viewed by 3124
Abstract
Broad Copy Number Gains (BCNGs) are copy-number increases of chromosomes or large segments of chromosomal arms. Publicly-available single-nucleotide polymorphism (SNP) array and RNA-Seq data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) consortium allowed us to design better control groups [...] Read more.
Broad Copy Number Gains (BCNGs) are copy-number increases of chromosomes or large segments of chromosomal arms. Publicly-available single-nucleotide polymorphism (SNP) array and RNA-Seq data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) consortium allowed us to design better control groups in order to identify changes in expression due to highly recurrent BCNGs (in chromosomes 20, 8, 7, 13). We identified: (1) Overexpressed Transcripts (OverT), transcripts whose expression increases in “COAD groups bearing a specific BCNG” in comparison to “control COAD groups” not bearing it, and (2) up-regulated/down-regulated transcripts, transcripts whose expression increases/decreases in COAD groups in comparison to normal colon tissue. An analysis of gene expression reveals a correlation between the density of up-regulated genes per selected chromosome and the recurrence rate of their BCNGs. We report an enrichment of gained enhancer activity and of cancer fitness genes among OverT genes. These results support the hypothesis that the chromosomal density of overexpressed cancer fitness genes might play a significant role in the selection of gained chromosomes during cancer evolution. Analysis of functional pathways associated with OverT suggest that some multi-subunit protein complexes (eIF2, eIF3, CSTF and CPSF) are candidate targets for silencing transcriptional therapy. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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14 pages, 2833 KiB  
Article
ESRP1 Induces Cervical Cancer Cell G1-Phase Arrest Via Regulating Cyclin A2 mRNA Stability
by Zhi-Hong Chen, Ya-Jie Jing, Jian-Bo Yu, Zai-Shu Jin, Zhu Li, Ting-Ting He and Xiu-Zhen Su
Int. J. Mol. Sci. 2019, 20(15), 3705; https://doi.org/10.3390/ijms20153705 - 29 Jul 2019
Cited by 16 | Viewed by 3344
Abstract
Accumulating evidence indicates that epithelial splicing regulatory protein 1 (ESRP1) can inhibit the epithelial-to-mesenchymal transition (EMT), thus playing a central role in regulating the metastatic progression of tumors. However, it is still not clear whether ESRP1 directly influences the cell cycle, or what [...] Read more.
Accumulating evidence indicates that epithelial splicing regulatory protein 1 (ESRP1) can inhibit the epithelial-to-mesenchymal transition (EMT), thus playing a central role in regulating the metastatic progression of tumors. However, it is still not clear whether ESRP1 directly influences the cell cycle, or what the possible underlying molecular mechanisms are. In this study, we showed that ESRP1 protein levels were significantly correlated with the Ki-67 proliferative index (r = −0.521; p < 0.01), and that ESRP1 overexpression can significantly inhibit cervical carcinoma cell proliferation and induced G1-phase arrest by downregulating cyclin A2 expression. Importantly, ESRP1 can bind to GGUGGU sequence in the 3′UTR of the cyclin A2 mRNA, and ESRP1 overexpression significantly decreases the stability of the cyclin A2 mRNA. In addition, our experimental results confirm that ESRP1 overexpression results in enhanced CDC20 expression, which is known to be responsible for cyclin A2 degradation. This study provides the first evidence that ESRP1 overexpression induces G1-phase cell cycle arrest via reducing the stability of the cyclin A2 mRNA, and inhibits cervical carcinoma cell proliferation. The findings suggest that the ESRP1/cyclin A2 regulatory axis may be essential as a regulator of cell proliferation, and may thus represent an attractive target for cervical cancer prevention and treatment. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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8 pages, 2034 KiB  
Article
The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer
by Charlotte Dahlem, Ahmad Barghash, Philip Puchas, Johannes Haybaeck and Sonja M. Kessler
Int. J. Mol. Sci. 2019, 20(13), 3204; https://doi.org/10.3390/ijms20133204 - 29 Jun 2019
Cited by 56 | Viewed by 4210
Abstract
The insulin-like growth factor 2 (IGF2) mRNA binding protein IMP2 (IGF2BP2) is an oncogenic protein known to be overexpressed in different tumor types. Pancreatic cancer is a very lethal cancer that requires early diagnosis and new treatment options. The aim of [...] Read more.
The insulin-like growth factor 2 (IGF2) mRNA binding protein IMP2 (IGF2BP2) is an oncogenic protein known to be overexpressed in different tumor types. Pancreatic cancer is a very lethal cancer that requires early diagnosis and new treatment options. The aim of our study was to investigate the role of IMP2 in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). IMP2 was significantly overexpressed in a human precursor (PanIN) lesions suggesting IMP2 as a marker for early stages of PDAC. In a PDAC cohort of matched normal and tumor samples IMP2 showed overexpression in tumor tissues compared with normal pancreatic tissue. Strict correlation analysis (threshold R2 > 0.75) revealed 22 genes highly positively and 9 genes highly negatively correlating with IMP2. Besides genes involved in the inhibition of apoptosis (Bcl-XL), especially factors involved in ubiquitination were strongly correlated with IMP2 expression: SMURF1 and FBXO45. Moreover, protein kinase C (PKC) signaling pathway was distinctly affected: DXS1179E encoding PKC iota, PKC substrate PLEK2, and inositol triphosphate receptor IP3R3 were positively correlated with IMP2 expression. Besides tumor initiation, IMP2 also seemed to have an impact on tumor progression. TGF-β treatment of Panc-1 pancreatic cancer cells to induce epithelial-mesenchymal transition (EMT) was accompanied by increased IMP2 expression. EMT is important for cancer cells to gain migratory and invasive potential, which is essential for metastasis. Concordantly, circulating tumor cells showed higher IMP2 levels as compared with normal tissue from tumor origin and with normal hematological cells. Accordingly, IMP2 protein levels correlated with poor survival. In conclusion, as IMP2 seems to promote tumor progression of PDAC, it might be an interesting diagnostic and prognostic marker as well as a novel target for the treatment of PDAC. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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17 pages, 2608 KiB  
Article
HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity
by Sylvester Larsen, Johanne Davidsen, Katja Dahlgaard, Ole B. Pedersen and Jesper T. Troelsen
Int. J. Mol. Sci. 2019, 20(12), 2981; https://doi.org/10.3390/ijms20122981 - 18 Jun 2019
Cited by 11 | Viewed by 3761
Abstract
The Hippo pathway is important for tissue homeostasis, regulation of organ size and growth in most tissues. The co-transcription factor yes-associated protein 1 (YAP1) serves as a main downstream effector of the Hippo pathway and its dysregulation increases cancer development and blocks colonic [...] Read more.
The Hippo pathway is important for tissue homeostasis, regulation of organ size and growth in most tissues. The co-transcription factor yes-associated protein 1 (YAP1) serves as a main downstream effector of the Hippo pathway and its dysregulation increases cancer development and blocks colonic tissue repair. Nevertheless, little is known about the transcriptional regulation of YAP1 in intestinal cells. The aim of this study to identify gene control regions in the YAP1 gene and transcription factors important for intestinal expression. Bioinformatic analysis of caudal type homeobox 2 (CDX2) and hepatocyte nuclear factor 4 alpha (HNF4α) chromatin immunoprecipitated DNA from differentiated Caco-2 cells revealed potential intragenic enhancers in the YAP1 gene. Transfection of luciferase-expressing YAP1 promoter-reporter constructs containing the potential enhancer regions validated one potent enhancer of the YAP1 promoter activity in Caco-2 and T84 cells. Two potential CDX2 and one HNF4α binding sites were identified in the enhancer by in silico transcription factor binding site analysis and protein-DNA binding was confirmed in vitro using electrophoretic mobility shift assay. It was found by chromatin immunoprecipitation experiments that CDX2 and HNF4α bind to the YAP1 enhancer in Caco-2 cells. These results reveal a previously unknown enhancer of the YAP1 promoter activity in the YAP1 gene, with importance for high expression levels in intestinal epithelial cells. Additionally, CDX2 and HNF4α binding are important for the YAP1 enhancer activity in intestinal epithelial cells. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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16 pages, 2451 KiB  
Article
New Insights into the Role of Polybromo-1 in Prostate Cancer
by Sara T. S. Mota, Lara Vecchi, Mariana A. P. Zóia, Fabrícia M. Oliveira, Douglas A. Alves, Bruno C. Dornelas, Stephania M. Bezerra, Victor P. Andrade, Yara C. P. Maia, Adriana F. Neves, Luiz Ricardo Goulart and Thaise G. Araújo
Int. J. Mol. Sci. 2019, 20(12), 2852; https://doi.org/10.3390/ijms20122852 - 12 Jun 2019
Cited by 11 | Viewed by 3442
Abstract
The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the [...] Read more.
The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased PBRM1 mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-β, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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15 pages, 2599 KiB  
Article
Increased FLYWCH1 Expression is Negatively Correlated with Wnt/β-catenin Target Gene Expression in Acute Myeloid Leukemia Cells
by Amany Almars, Panagiota S. Chondrou, Emenike K. Onyido, Sheema Almozyan, Claire Seedhouse, Roya Babaei-Jadidi and Abdolrahman S. Nateri
Int. J. Mol. Sci. 2019, 20(11), 2739; https://doi.org/10.3390/ijms20112739 - 04 Jun 2019
Cited by 7 | Viewed by 4159
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous clonal malignancy of hematopoietic progenitor cells. The Wnt pathway and its downstream targets are tightly regulated by β-catenin. We recently discovered a new protein, FLYWCH1, which can directly bind nuclear β-catenin. Herein, we studied the FLYWCH1/β-catenin [...] Read more.
Acute myeloid leukaemia (AML) is a heterogeneous clonal malignancy of hematopoietic progenitor cells. The Wnt pathway and its downstream targets are tightly regulated by β-catenin. We recently discovered a new protein, FLYWCH1, which can directly bind nuclear β-catenin. Herein, we studied the FLYWCH1/β-catenin pathway in AML cells using qRT-PCR, Western blot, and immunofluorescence assays. In addition, the stemness activity and cell cycle were analysed by the colony-forming unit (CFU) using methylcellulose-based and Propidium iodide/flow cytometry assays. We found that FLYWCH1 mRNA and protein were differentially expressed in the AML cell lines. C-Myc, cyclin D1, and c-Jun expression decreased in the presence of higher FLYWCH1 expression, and vice versa. There appeared to be the loss of FLYWCH1 expression in dividing cells. The sub-G0 phase was prolonged and shortened in the low and high FLYWCH1 expression cell lines, respectively. The G0/G1 arrest correlated with FLYWCH1-expression, and these cell lines also formed colonies, whereas the low FLYWCH1 expression cell lines could not. Thus, FLYWCH1 functions as a negative regulator of the Wnt/β-catenin pathway in AML. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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19 pages, 3496 KiB  
Article
A Comprehensive Bioinformatics Analysis of UBE2C in Cancers
by Hassan Dastsooz, Matteo Cereda, Daniela Donna and Salvatore Oliviero
Int. J. Mol. Sci. 2019, 20(9), 2228; https://doi.org/10.3390/ijms20092228 - 07 May 2019
Cited by 70 | Viewed by 7952
Abstract
Ubiquitination is one of the main post-translational modification of proteins. It plays key roles in a broad range of cellular functions, including protein degradation, protein interactions, and subcellular location. In the ubiquitination system, different proteins are involved and their dysregulation can lead to [...] Read more.
Ubiquitination is one of the main post-translational modification of proteins. It plays key roles in a broad range of cellular functions, including protein degradation, protein interactions, and subcellular location. In the ubiquitination system, different proteins are involved and their dysregulation can lead to various human diseases, including cancers. By using data available from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we here show that the ubiquitin conjugating enzyme, E2C (UBE2C), is overexpressed in all 27 cancers we investigated. UBE2C expression is significantly higher in late-stage tumors, which might indicate its involvement in tumor progression and invasion. This study also revealed that patients with higher UBE2C levels showed a shorter overall survival (OS) time and worse OS prognosis. Moreover, our data show that UBE2C higher-expression leads to worse disease-free survival prognosis (DFS), indicating that UBE2C overexpression correlates with poor clinical outcomes. We also identified genes with positive correlations with UBE2C in several cancers. We found a number of poorly studied genes (family with sequence similarity 72-member D, FAM72D; meiotic nuclear divisions 1, MND1; mitochondrial fission regulator 2, MTFR2; and POC1 centriolar protein A, POC1A) whose expression correlates with UBE2C. These genes might be considered as new targets for cancers therapies since they showed overexpression in several cancers and correlate with worse OS prognosis. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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11 pages, 1948 KiB  
Communication
HER2 Upregulates ATF4 to Promote Cell Migration via Activation of ZEB1 and Downregulation of E-Cadherin
by Peng Zeng, Shengnan Sun, Rui Li, Zhi-Xiong Xiao and Hu Chen
Int. J. Mol. Sci. 2019, 20(9), 2223; https://doi.org/10.3390/ijms20092223 - 06 May 2019
Cited by 37 | Viewed by 4980
Abstract
HER2 (human epidermal growth factor receptor 2) activation is critical in breast cancer development. HER2 promotes cell proliferation, angiogenesis, survival, and metastasis by activation of PI3K/Akt, Ras/MEK/ERK, and JAK/STAT pathways. However, beyond these signaling molecules, the key proteins underlining HER2-mediated metastasis remain elusive. [...] Read more.
HER2 (human epidermal growth factor receptor 2) activation is critical in breast cancer development. HER2 promotes cell proliferation, angiogenesis, survival, and metastasis by activation of PI3K/Akt, Ras/MEK/ERK, and JAK/STAT pathways. However, beyond these signaling molecules, the key proteins underlining HER2-mediated metastasis remain elusive. ATF4 (Activating transcription factor 4), a critical regulator in unfolded protein response (UPR), is implicated in cell migration and tumor metastasis. In this study, we demonstrate that HER2 upregulated ATF4 expression at both mRNA and protein levels, resulting in cell migration increased. In addition, ATF4 upregulated ZEB1 (Zinc finger E-box-binding homeobox 1) and suppressed E-cadherin expression resulting in promoting cell migration. Restoration of E-cadherin expression effectively inhibited HER2- or ATF4-mediated cell migration. In addition, upregulated expression of ATF4 was found in HER2-positive breast cancer specimens. Together, this study demonstrates that ATF4-ZEB1 is important for HER2-mediated cell migration and suggests that ATF4-ZEB1 may be potential therapeutic targets for breast cancer metastasis. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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17 pages, 3224 KiB  
Article
STAT3 Post-Translational Modifications Drive Cellular Signaling Pathways in Prostate Cancer Cells
by Rossana Cocchiola, Elisabetta Rubini, Fabio Altieri, Silvia Chichiarelli, Giuliano Paglia, Donatella Romaniello, Stefania Carissimi, Alessandra Giorgi, Flavia Giamogante, Alberto Macone, Giacomo Perugia, Aymone Gurtner and Margherita Eufemi
Int. J. Mol. Sci. 2019, 20(8), 1815; https://doi.org/10.3390/ijms20081815 - 12 Apr 2019
Cited by 22 | Viewed by 4880
Abstract
STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays [...] Read more.
STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays specific cellular conditions: inflammation is predominant in tumor’s early stage, whereas oxidative stress is typical of clinically advanced PCa. The aim of this research is to assess the correspondence between the stimulus-specificity of STAT3 PTMs and definite STAT3-mediated transcriptional programs, in order to identify new suitable pharmacological targets for PCa treatment. Experiments were performed on less-aggressive LNCaP and more aggressive DU-145 cell lines, simulating inflammatory and oxidative-stress conditions. Cellular studies confirmed pY705-STAT3 as common denominator of all STAT3-mediated signaling. In addition, acK685-STAT3 was found in response to IL-6, whereas glutC328/542-STAT3 and pS727-STAT3 occurred upon tert-butyl hydroperoxyde (tBHP) treatment. Obtained results also provided evidence of an interplay between STAT3 PTMs and specific protein interactors such as P300 and APE1/Ref-1. In accordance with these outcomes, mRNA levels of STAT3-target genes seemed to follow the differing STAT3 PTMs. These results highlighted the role of STAT3 and its PTMs as drivers in the progression of PCa. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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19 pages, 3646 KiB  
Article
BCAS2 Enhances Carcinogenic Effects of Estrogen Receptor Alpha in Breast Cancer Cells
by Ángel Salmerón-Hernández, María Yamilet Noriega-Reyes, Albert Jordan, Noemi Baranda-Avila and Elizabeth Langley
Int. J. Mol. Sci. 2019, 20(4), 966; https://doi.org/10.3390/ijms20040966 - 22 Feb 2019
Cited by 11 | Viewed by 3437
Abstract
Estrogen receptor alpha (ERα) has an established role in breast cancer biology. Transcriptional activation by ERα is a multistep process modulated by coactivator and corepressor proteins. Breast Cancer Amplified Sequence 2 (BCAS2), is a poorly studied ERα coactivator. In this work, we characterize [...] Read more.
Estrogen receptor alpha (ERα) has an established role in breast cancer biology. Transcriptional activation by ERα is a multistep process modulated by coactivator and corepressor proteins. Breast Cancer Amplified Sequence 2 (BCAS2), is a poorly studied ERα coactivator. In this work, we characterize some of the mechanisms through which this protein increases ERα activity and how this promotes carcinogenic processes in breast cancer cells. Using protein-protein interaction and luciferase assays we show that BCAS2 interacts with ERα both in vitro and in vivo and upregulates transcriptional activation of ERα directly through its N-terminal region (AF-1) and indirectly through its C-terminal (AF-2) region, acting in concert with AF-2 interacting coactivators. Elevated expression of BCAS2 positively affects proliferation, clonogenicity and migration of breast cancer cells and directly activates ERα regulated genes which have been shown to play a role in tumor growth and progression. Finally, we used signal transduction pathway inhibitors to elucidate how BCAS2 is regulated in these cells and observed that BCAS2 is preferentially regulated by the PI3K/AKT signaling pathway. BCAS2 is an AF-1 coactivator of ERα whose overexpression promotes carcinogenic processes, suggesting an important role in the development of estrogen-receptor positive breast cancer. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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16 pages, 3458 KiB  
Article
IL-8 Secreted from M2 Macrophages Promoted Prostate Tumorigenesis via STAT3/MALAT1 Pathway
by Tingjin Zheng, Guoxing Ma, Mingqing Tang, Zhongwan Li and Ruian Xu
Int. J. Mol. Sci. 2019, 20(1), 98; https://doi.org/10.3390/ijms20010098 - 27 Dec 2018
Cited by 60 | Viewed by 6554
Abstract
Prostate cancer (PCa) is a major health problem in males. Metastasis-associated with lung adenocarcinoma transcript-1 (MALAT1), which is overexpressed in PCa tissue, is associated with physiological and pathological conditions of PCa. M2 macrophages are major immune cells abundant in the tumor microenvironment. However, [...] Read more.
Prostate cancer (PCa) is a major health problem in males. Metastasis-associated with lung adenocarcinoma transcript-1 (MALAT1), which is overexpressed in PCa tissue, is associated with physiological and pathological conditions of PCa. M2 macrophages are major immune cells abundant in the tumor microenvironment. However, it remains unknown whether M2 macrophages are involved in the effects or not, and molecular mechanisms of MALAT1 on PCa progression have not yet been comprehensively explored. Here we reported that, M2 macrophages (PMA/IL-4 treated THP1) induced MALAT1 expression in PCa cell lines. Knockdown MALAT1 expression level in PCa cell lines inhibited cellular proliferation, invasion, and tumor formation. Further mechanistic dissection revealed that M2 macrophages secreted IL-8 was sufficient to drive up MALAT1 expression level via activating STAT3 signaling pathway. Additional chromatin immunoprecipitation (ChIP) and luciferase reporter assays displayed that STAT3 could bind to the MALAT1 promoter region and transcriptionally stimulate the MALAT1 expression. In summary, our present study identified the IL-8/STAT3/MALAT1 axis as key regulators during prostate tumorigenesis and therefore demonstrated a new mechanism for the MALAT1 transcriptional regulation. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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28 pages, 2271 KiB  
Review
Fusion Transcripts of Adjacent Genes: New Insights into the World of Human Complex Transcripts in Cancer
by Vincenza Barresi, Ilaria Cosentini, Chiara Scuderi, Salvatore Napoli, Virginia Di Bella, Giorgia Spampinato and Daniele Filippo Condorelli
Int. J. Mol. Sci. 2019, 20(21), 5252; https://doi.org/10.3390/ijms20215252 - 23 Oct 2019
Cited by 12 | Viewed by 4131
Abstract
The awareness of genome complexity brought a radical approach to the study of transcriptome, opening eyes to single RNAs generated from two or more adjacent genes according to the present consensus. This kind of transcript was thought to originate only from chromosomal rearrangements, [...] Read more.
The awareness of genome complexity brought a radical approach to the study of transcriptome, opening eyes to single RNAs generated from two or more adjacent genes according to the present consensus. This kind of transcript was thought to originate only from chromosomal rearrangements, but the discovery of readthrough transcription opens the doors to a new world of fusion RNAs. In the last years many possible intergenic cis-splicing mechanisms have been proposed, unveiling the origins of transcripts that contain some exons of both the upstream and downstream genes. In some cases, alternative mechanisms, such as trans-splicing and transcriptional slippage, have been proposed. Five databases, containing validated and predicted Fusion Transcripts of Adjacent Genes (FuTAGs), are available for the scientific community. A comparative analysis revealed that two of them contain the majority of the results. A complete analysis of the more widely characterized FuTAGs is provided in this review, including their expression pattern in normal tissues and in cancer. Gene structure, intergenic splicing patterns and exon junction sequences have been determined and here reported for well-characterized FuTAGs. The available functional data and the possible roles in cancer progression are discussed. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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21 pages, 906 KiB  
Review
Long Non-coding RNAs as Important Biomarkers in Laryngeal Cancer and Other Head and Neck Tumours
by Alessia Maria Cossu, Laura Mosca, Silvia Zappavigna, Gabriella Misso, Marco Bocchetti, Federica De Micco, Lucio Quagliuolo, Marina Porcelli, Michele Caraglia and Mariarosaria Boccellino
Int. J. Mol. Sci. 2019, 20(14), 3444; https://doi.org/10.3390/ijms20143444 - 12 Jul 2019
Cited by 67 | Viewed by 4662
Abstract
Head and neck carcinoma (HNC) is a heterogeneous disease encompassing a variety of tumors according to the origin. Laryngeal cancer (LC) represents one of the most frequent tumors in the head and neck region. Despite clinical studies and advance in treatment, satisfactory curative [...] Read more.
Head and neck carcinoma (HNC) is a heterogeneous disease encompassing a variety of tumors according to the origin. Laryngeal cancer (LC) represents one of the most frequent tumors in the head and neck region. Despite clinical studies and advance in treatment, satisfactory curative strategy has not yet been reached. Therefore, there is an urgent need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as suitable therapeutic targets. Long non-coding RNAs (lncRNA) are reported as important regulators of gene expression and represent an innovative pharmacological application as molecular biomarkers in cancer. The purpose of this review is to discuss the most relevant epigenetic and histological prognostic biomarkers in HNC, with particular focus on LC. We summarize the emerging roles of long non-coding RNAs in HNC and LC development and their possible use in early diagnosis. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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21 pages, 676 KiB  
Review
Ubiquitination and Long Non-coding RNAs Regulate Actin Cytoskeleton Regulators in Cancer Progression
by Xuda Ma, Yamei Dang, Xiaowen Shao, Xuechun Chen, Fei Wu and Yongmei Li
Int. J. Mol. Sci. 2019, 20(12), 2997; https://doi.org/10.3390/ijms20122997 - 19 Jun 2019
Cited by 30 | Viewed by 4645
Abstract
Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs [...] Read more.
Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs (LIM domain kinases), and SSH1 (slingshot family protein phosphate 1). Ubiquitination, as a ubiquitous post-transcriptional modification, deceases protein levels of actin cytoskeleton regulatory factors and thereby modulates the actin cytoskeleton. There is increasing evidence showing cytoskeleton regulation by long noncoding RNAs (lncRNAs) in cancer metastasis. However, which E3 ligases are activated for the ubiquitination of actin-cytoskeleton regulators involved in tumor metastasis remains to be fully elucidated. Moreover, it is not clear how lncRNAs influence the expression of actin cytoskeleton regulators. Here, we summarize physiological and pathological mechanisms of lncRNAs and ubiquitination control mediators of actin cytoskeleton regulators which that are involved in tumorigenesis and tumor progression. Finally, we briefly discuss crosstalk between ubiquitination and lncRNA control mediators of actin-cytoskeleton regulators in cancer. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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18 pages, 1625 KiB  
Review
p63 at the Crossroads between Stemness and Metastasis in Breast Cancer
by Veronica Gatti, Lucilla Bongiorno-Borbone, Claudia Fierro, Margherita Annicchiarico-Petruzzelli, Gerry Melino and Angelo Peschiaroli
Int. J. Mol. Sci. 2019, 20(11), 2683; https://doi.org/10.3390/ijms20112683 - 31 May 2019
Cited by 46 | Viewed by 8563
Abstract
After lung cancer, breast cancer (BC) is the most frequent cause of cancer death among women, worldwide. Although advances in screening approaches and targeted therapeutic agents have decreased BC incidence and mortality, over the past five years, triple-negative breast cancer (TNBC) remains the [...] Read more.
After lung cancer, breast cancer (BC) is the most frequent cause of cancer death among women, worldwide. Although advances in screening approaches and targeted therapeutic agents have decreased BC incidence and mortality, over the past five years, triple-negative breast cancer (TNBC) remains the breast cancer subtype that displays the worst prognosis, mainly due to the lack of clinically actionable targets. Genetic and molecular profiling has unveiled the high intrinsic heterogeneity of TNBC, with the basal-like molecular subtypes representing the most diffuse TNBC subtypes, characterized by the expression of basal epithelial markers, such as the transcription factor p63. In this review, we will provide a broad picture on the physiological role of p63, in maintaining the basal epithelial identity, as well as its involvement in breast cancer progression, emphasizing its relevance in tumor cell invasion and stemness. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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14 pages, 1890 KiB  
Review
Roles of MicroRNA-34a in Epithelial to Mesenchymal Transition, Competing Endogenous RNA Sponging and Its Therapeutic Potential
by Dongsong Nie, Jiewen Fu, Hanchun Chen, Jingliang Cheng and Junjiang Fu
Int. J. Mol. Sci. 2019, 20(4), 861; https://doi.org/10.3390/ijms20040861 - 16 Feb 2019
Cited by 40 | Viewed by 5606
Abstract
MicroRNA-34a (miR-34a), a tumor suppressor, has been reported to be dysregulated in various human cancers. MiR-34a is involves in certain epithelial-mesenchymal transition (EMT)-associated signal pathways to repress tumorigenesis, cancer progression, and metastasis. Due to the particularity of miR-34 family in tumor-associated EMT, the [...] Read more.
MicroRNA-34a (miR-34a), a tumor suppressor, has been reported to be dysregulated in various human cancers. MiR-34a is involves in certain epithelial-mesenchymal transition (EMT)-associated signal pathways to repress tumorigenesis, cancer progression, and metastasis. Due to the particularity of miR-34 family in tumor-associated EMT, the significance of miR-34a is being increasingly recognized. Competing endogenous RNA (ceRNA) is a novel concept involving mRNA, circular RNA, pseudogene transcript, and long noncoding RNA regulating each other’s expressions using microRNA response elements to compete for the binding of microRNAs. Studies showed that miR-34a is efficient for cancer therapy. Here, we provide an overview of the function of miR-34a in tumor-associated EMT. ceRNA hypothesis plays an important role in miR-34a regulation in EMT, cancer progression, and metastasis. Its potential roles and challenges as a microRNA therapeutic candidate are discussed. As the negative effect on cancer progression, miR-34a should play crucial roles in clinical diagnosis and cancer therapy. Full article
(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)
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