bims-ectoca 2022-04-17 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–04–17
nineteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer.
Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development.
Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering.
FOXC1 Binds Enhancers and Promotes Cisplatin Resistance in Bladder Cancer.
Phosphorylation analysis of the Hippo-YAP pathway using Phos-tag.
Experimental development of the epigenomic library construction method to elucidate the epigenetic diversity and causal relationship between epigenome and transcriptome at a single-cell level.
Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.
The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells.
Pinpointing Cancer Sub-Type Specific Metabolic Tasks Facilitates Identification of Anti-cancer Targets.
Genetic and Molecular Characterization Revealed the Prognosis Efficiency of Histone Acetylation in Pan-Digestive Cancers.
Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer.
Histone Demethylase GASC1 Inhibitor Targeted GASC1 Gene to Inhibit the Malignant Transformation of Esophageal Cancer through the NOTCH-MAPK Signaling Pathway.
Identification of Immune-Related lncRNA Pairs and Construction and Validation of a New Prognostic Signature of Colon Cancer.
Pan-cancer analysis of mutations in open chromatin regions and their possible association with cancer pathogenesis.
Promoter antisense RNAs: beyond transcription by-products of active promoters.
Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer.
Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA.
Roles of ARID1A variations in colorectal cancer: a collaborative review.
Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis.

Cells. 2022 Mar 25. pii: 1113. [Epub ahead of print]11(7):

Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer.

Joyce Taylor-Papadimitriou, Joy M Burchell.

  Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.

Keywords:  Polycomb; Trithorax; cancer; epigenetics; histone demethylases; histone methylases

DOI:  https://doi.org/10.3390/cells11071113
Front Oncol. 2022 ;12 848221

Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development.

Ye Jin, Tianjia Liu, Haoming Luo, Yangyang Liu, Da Liu.

  Dysregulation of the epigenetic enzyme-mediated transcription of oncogenes or tumor suppressor genes is closely associated with the occurrence, progression, and prognosis of tumors. Based on the reversibility of epigenetic mechanisms, small-molecule compounds that target epigenetic regulation have become promising therapeutics. These compounds target epigenetic regulatory enzymes, including DNA methylases, histone modifiers (methylation and acetylation), enzymes that specifically recognize post-translational modifications, chromatin-remodeling enzymes, and post-transcriptional regulators. Few compounds have been used in clinical trials and exhibit certain therapeutic effects. Herein, we summarize the classification and therapeutic roles of compounds that target epigenetic regulatory enzymes in cancer treatment. Finally, we highlight how the natural compounds berberine and ginsenosides can target epigenetic regulatory enzymes to treat cancer.

Keywords:  cancer therapeutics; epidrug development; epigenetic regulatory enzymes; inhibitors; small molecule

DOI:  https://doi.org/10.3389/fonc.2022.848221
Trends Biochem Sci. 2022 May;pii: S0968-0004(22)00061-5. [Epub ahead of print]47(5): 417-432

Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering.

Kierra A Franklin, Cara E Shields, Karmella A Haynes.

  Chromatin is a system of proteins and DNA that regulates chromosome organization and gene expression in eukaryotes. Essential features that support these processes include biochemical marks on histones and DNA, 'writer' enzymes that generate or remove these marks and proteins that translate the marks into transcriptional regulation: reader-effectors. Here, we review recent studies that reveal how reader-effectors drive chromatin-mediated processes. Advances in proteomics and epigenomics have accelerated the discovery of chromatin marks and their correlation with gene states, outpacing our understanding of the corresponding reader-effectors. Therefore, we summarize the current state of knowledge and open questions about how reader-effectors impact cellular function and human disease and discuss how synthetic biology can deepen our knowledge of reader-effector activity.

Keywords:  cell developmental disease; chromatin modifications; epigenome; protein engineering; signal integration; transcriptional regulation

DOI:  https://doi.org/10.1016/j.tibs.2022.03.002
Cancers (Basel). 2022 Mar 28. pii: 1717. [Epub ahead of print]14(7):

FOXC1 Binds Enhancers and Promotes Cisplatin Resistance in Bladder Cancer.

Yi-Tsung Lu, Tong Xu, Maheen Iqbal, Tien-Chan Hsieh, Zhifei Luo, Gangning Liang, Peggy J Farnham, Suhn K Rhie, Amir Goldkorn.

  Chemotherapy resistance is traditionally attributed to DNA mutations that confer a survival advantage under drug selection pressure. However, in bladder cancer and other malignancies, we and others have previously reported that cancer cells can convert spontaneously to an aggressive drug-resistant phenotype without prior drug selection or mutational events. In the current work, we explored possible epigenetic mechanisms behind this phenotypic plasticity. Using Hoechst dye exclusion and flow cytometry, we isolated the aggressive drug-resistant cells and analyzed their chromatin accessibility at regulatory elements. Compared to the rest of the cancer cell population, the aggressive drug-resistant cells exhibited enhancer accessibility changes. In particular, we found that differentially accessible enhancers were enriched for the FOXC1 transcription factor motif, and that FOXC1 was the most significantly overexpressed gene in aggressive drug-resistant cells. ChIP-seq analysis revealed that differentially accessible enhancers in aggressive drug-resistant cells had a higher FOXC1 binding, which regulated the expression of adjacent cancer-relevant genes like ABCB1 and ID3. Accordingly, cisplatin treatment of bladder cancer cells led to an increased FOXC1 expression, which mediated cell survival and conversion to a drug-resistant phenotype. Collectively, these findings suggest that FOXC1 contributes to phenotypic plasticity by binding enhancers and promoting a mutation-independent shift towards cisplatin resistance in bladder cancer.

Keywords:  FOXC1; bladder cancer; chromatin accessibility; drug resistance; enhancer activation

DOI:  https://doi.org/10.3390/cancers14071717
J Proteomics. 2022 Apr 12. pii: S1874-3919(22)00105-1. [Epub ahead of print] 104582

Phosphorylation analysis of the Hippo-YAP pathway using Phos-tag.

Cho-Long Kim, Su-Bin Lim, Kyeongseob Kim, Han-Sol Jeong, Jung-Soon Mo.

  Phosphorylation is an essential regulatory mechanism in cells that modifies diverse substrates, such as proteins, carbohydrates, lipids, and nucleotides. Protein phosphorylation regulates function, subcellular localization, and protein-protein interactions. Protein kinases and phosphatases catalyze this reversible mechanism, subsequently influencing signal transduction. The dysregulation of protein phosphorylation leads to many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Therefore, analyzing the phosphorylation status and identifying protein phosphorylation sites are critical for elucidating the biological functions of specific phosphorylation events. Unraveling the critical phosphorylation events associated with diseases and specific signaling pathways is promising for drug discovery. To date, highly accurate and sensitive approaches have been developed to detect the phosphorylation status of proteins. In this review, we discuss the application of Phos-tag to elucidate the biological functions of Hippo pathway components, with emphasis on the identification and quantitation of protein phosphorylation under physiological and pathological conditions. SIGNIFICANCE: We here provide a comprehensive overview of Phos-tag technique-based strategies to identify phosphorylated proteins at the cellular level in the Hippo-YAP pathway that comprises a major driving force for cellular homeostasis. We clarify the links of applying Phos-tag in elucidating the biological functions of the Hippo pathway components with particular attention to the identification and quantitation of protein phosphorylation under physiological and pathological conditions. We believe that our paper will make a significant contribution to the literature because these detailed phosphorylation modifications and functional diversity of the Hippo pathway components in physiological and pathological processes are only beginning to come to the fore, highlighting the potential for discovering new therapeutic targets. Moreover, this line of research can provide further insight into the inextricable link between phos-tag applications as a molecular tool and cellular signaling modality, offering new directions for an integrated research program toward understanding cellular regulation at the molecular level. Given the broad research and practical applications, we believe that this paper will be of interest to the readership of your journal.

Keywords:  Hippo pathway; Mobility shift; Phos-tag; Post-translational modification; Protein Phosphorylation; YAP

DOI:  https://doi.org/10.1016/j.jprot.2022.104582
Genomics Inform. 2022 Mar;20(1): e2

Experimental development of the epigenomic library construction method to elucidate the epigenetic diversity and causal relationship between epigenome and transcriptome at a single-cell level.

Kyunghyuk Park, Min Chul Jeon, Bokyung Kim, Bukyoung Cha, Jong-Il Kim.

  The method of single-cell RNA sequencing has been rapidly developed, and numerous experiments have been conducted over the past decade. Their results allow us to recognize various subpopulations and rare cell states in tissues, tumors, and immune systems that are previously unidentified, and guide us to understand fundamental biological processes that determine cell identity based on single-cell gene expression profiles. However, it is still challenging to understand the principle of comprehensive gene regulation that determines the cell fate only with transcriptome, a consequential output of the gene expression program. To elucidate the mechanisms related to the origin and maintenance of comprehensive single-cell transcriptome, we require a corresponding single-cell epigenome, which is a differentiated information of each cell with an identical genome. This review deals with the current development of single-cell epigenomic library construction methods, including multi-omics tools with crucial factors and additional requirements in the future focusing on DNA methylation, chromatin accessibility, and histone post-translational modifications. The study of cellular differentiation and the disease occurrence at a single-cell level has taken the first step with single-cell transcriptome and is now taking the next step with single-cell epigenome.

Keywords:  DNA methylation; cellular heterogeneity; chromatin accessibility; histone post-translational modifications (PTMs); single-cell epigenome; single-cell multiome

DOI:  https://doi.org/10.5808/gi.21078
Trends Biochem Sci. 2022 Apr 06. pii: S0968-0004(22)00067-6. [Epub ahead of print]

Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.

Di Zhu, Xinyu Li, Ye Tian.

  Age-associated changes in mitochondria are closely involved in aging. Apart from the established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear (mito-nuclear) communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging. Here, we summarize recent studies on the mechanisms by which mito-nuclear communication modulates epigenomes and their effects on regulating the aging process. Insights into understanding how mitochondrial metabolites serve as prolongevity signals and how aging affects this communication will help us develop interventions to promote longevity and health.

Keywords:  UPR(mt); aging; epigenetic regulation; longevity; mitochondrial metabolites; mitochondrial–nuclear communication

DOI:  https://doi.org/10.1016/j.tibs.2022.03.008
Int J Mol Sci. 2022 Mar 30. pii: 3801. [Epub ahead of print]23(7):

The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells.

Hongsen Liu, Tao Wei, Lin Sun, Tingting Wu, Fuqiang Li, Jianlei Zhao, Jinmeng Chu, Fei Wang, Yong Cai, Jingji Jin.

  The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase (HAT) complex acetylates histone H4 at lysine K5, K8, and K16. This complex shares several subunits with other epigenetic regulatory enzymes, which highlights the complexity of its intracellular function. However, the effect of the NSL HAT complex on the genome and target genes in human cells is still unclear. By using a CRISPR/Cas9-mediated NSL3-knockout 293T cell line and chromatin immunoprecipitation-sequencing (ChIP-Seq) approaches, we identified more than 100 genes as NSL HAT transcriptional targets, including several transcription factors, such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. We found here that the ChIP-Seq peaks of MOF and NSL3 co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. In addition, both the mRNA and protein expression levels of YY1 were regulated by silencing or overexpressing NSL HAT. Interestingly, the expression levels of cell division cycle 6, a downstream target gene of YY1, were regulated by MOF or NSL3. In addition, the suppressed clonogenic ability of HepG2 cells caused by siNSL3 was reversed by overexpressing YY1, suggesting the involvement of YY1 in NSL HAT functioning. Additionally, de novo motif analysis of MOF and NSL3 targets indicated that the NSL HAT complex may recognize the specific DNA-binding sites in the promoter region of target genes in order to regulate their transcription.

Keywords:  Yin Yang 1; cell proliferation; epigenetics; gene transcription; histone acetyltransferase; transcription factor

DOI:  https://doi.org/10.3390/ijms23073801
Front Med (Lausanne). 2022 ;9 872024

Pinpointing Cancer Sub-Type Specific Metabolic Tasks Facilitates Identification of Anti-cancer Targets.

Shuaishi Gao, Ziwei Dai, Hanyu Xu, Luhua Lai.

  Metabolic reprogramming is one of the hallmarks of tumorigenesis. Understanding the metabolic changes in cancer cells may provide attractive therapeutic targets and new strategies for cancer therapy. The metabolic states are not the same in different cancer types or subtypes, even within the same sample of solid tumors. In order to understand the heterogeneity of cancer cells, we used the Pareto tasks inference method to analyze the metabolic tasks of different cancers, including breast cancer, lung cancer, digestive organ cancer, digestive tract cancer, and reproductive cancer. We found that cancer subtypes haves different propensities toward metabolic tasks, and the biological significance of these metabolic tasks also varies greatly. Normal cells treat metabolic tasks uniformly, while different cancer cells focus on different pathways. We then integrated the metabolic tasks into the multi-objective genome-scale metabolic network model, which shows higher accuracy in the in silico prediction of cell states after gene knockout than the conventional biomass maximization model. The predicted potential single drug targets could potentially turn into biomarkers or drug design targets. We further implemented the multi-objective genome-scale metabolic network model to predict synthetic lethal target pairs of the Basal and Luminal B subtypes of breast cancer. By analyzing the predicted synthetic lethal targets, we found that mitochondrial enzymes are potential targets for drug combinations. Our study quantitatively analyzes the metabolic tasks of cancer and establishes cancer type-specific metabolic models, which opens a new window for the development of specific anti-cancer drugs and provides promising treatment plans for specific cancer subtypes.

Keywords:  cancer metabolism; metabolic network; metabolic task; multi-objective; synthetic lethality

DOI:  https://doi.org/10.3389/fmed.2022.872024
J Oncol. 2022 ;2022 3938652

Genetic and Molecular Characterization Revealed the Prognosis Efficiency of Histone Acetylation in Pan-Digestive Cancers.

Tao Zhang, Bofang Wang, Baohong Gu, Fei Su, Lin Xiang, Le Liu, Xuemei Li, Xueyan Wang, Lei Gao, Hao Chen.

The imbalance between acetylation and deacetylation of histone proteins, important for epigenetic modifications, is closely associated with various diseases, including cancer. However, knowledge regarding the modification of histones across the different types of digestive cancers is still lacking. The purpose of this research was to analyze the role of histone acetylation and deacetylation in pan-digestive cancers. We systematically characterized the molecular alterations and clinical relevance of 13 histone acetyltransferase (HAT) and 18 histone deacetylase (HDAC) genes in five types of digestive cancers, including esophageal carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. Recurrent mutations and copy number variation (CNV) were extensively found in acetylation-associated genes across pan-digestive cancers. HDAC9 and KAT6A showed widespread copy number amplification across five pan-digestive cancers, while ESCO2, EP300, and HDAC10 had prevalent copy number deletions. Accordingly, we found that HAT and HDAC genes correlated with multiple cancer hallmark-related pathways, especially the histone modification-related pathway, PRC2 complex pathway. Furthermore, the expression pattern of HAT and HDAC genes stratified patients with clinical benefit in hepatocellular carcinoma and pancreatic cancer. These results indicated that acetylation acts as a key molecular regulation of pan-digestive tumor progression.

DOI: https://doi.org/10.1155/2022/3938652
Cancers (Basel). 2022 Apr 02. pii: 1813. [Epub ahead of print]14(7):

Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer.

Marcin Nicoś, Paweł Krawczyk.

  Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.

Keywords:  NSCLC; clonal/subclonal alterations; driver mutations; metastases; tumor evolution

DOI:  https://doi.org/10.3390/cancers14071813
Ann Clin Lab Sci. 2022 Mar;52(2): 240-248

Histone Demethylase GASC1 Inhibitor Targeted GASC1 Gene to Inhibit the Malignant Transformation of Esophageal Cancer through the NOTCH-MAPK Signaling Pathway.

Qiong Li, Bin Qu, Haoming Shen, Hongyu Deng, Lisha Sun.

OBJECTIVE: Esophageal cancer is a common gastrointestinal tumor, with high incidence in our country. Histone demethylase 4 plays an important role in chromosome structural modification and gene expression regulation, becoming a new target for tumor treatment. GASC1 is an important member of the KDM4 family, closely related to the malignancy of tumors.
METHODS: Constructing the short hairpin interfering RNA plasmid and blank control plasmid of gene KDM4C (also known as GASC1), transfecting them into human esophageal squamous cell carcinoma cell lines (KYSE-150 and KYSE-30, respectively), and screening the best treatment concentration based on cell viability. Cell cloning experiments analyzed the proliferation characteristics of each group of cells. Cell migration and scratch healing experiments analyzed the tumor's malignant metastasis and invasion capabilities. Immunofluorescence analysis was used to test the expression characteristics of protein GASC1. Western blot was used to analyze protein Notch1, HIF1A, Flt-1, c-myc, c-fos expression in each group of cell lines.
RESULTS: In this experiment, caffeic acid and interfering RNA plasmids were added to regulate the expression level of GASC1 protein in each group. After that, a series of characterization methods were used to determine the positive correlation of the metastasis and proliferation ability of esophageal cancer cells with the expression level of GASC1 protein. The regulation of GASC1 protein was further proved by measuring the expression of each cancer-related protein.
CONCLUSION: GASC1 gene plays a crucial role in the progression of esophageal cancer. By inhibiting the expression of GASC1 gene, pathways closely related to cancer development such as NOTCH and MAPK will also be inhibited, which may ultimately control the malignant development.

Keywords: Esophageal cancer; GASC1; MAPK; NOTCH
Can J Gastroenterol Hepatol. 2022 ;2022 5827544

Identification of Immune-Related lncRNA Pairs and Construction and Validation of a New Prognostic Signature of Colon Cancer.

Minxian Xu, Qing Li, Jianfang Zhang, Hui Xie.

Background: More and more evidence has shown that immune-related long noncoding ribonucleic acid (irlncRNAs) is a potential prognostic factor for colon cancer. The relevant gene pair pattern can improve the sensitivity of the prognostic model. Therefore, our present study aimed to identify irlncRNA Pairs and construct and validate a new prognostic signature in colon cancer.
Methods: We downloaded the expression matrix of mRNA and lncRNA of patients with colon cancer and their clinical information from the public TCGA database. We obtained immune genes from the ImmPort database. Coexpression analysis was performed to identify irlncRNAs. We built an irlncRNA pair matrix by comparing the expression levels of each lncRNA pair in a cycle. Univariate Cox regression analysis, LASSO penalized regression analysis, and multivariate Cox regression analysis were performed to determine the final variables to construct the prognostic risk score model (a new signature). We draw the receiver operating characteristic (ROC) curves of the signature and clinical characteristics and determine the optimal cutoff value by the optimal Akaike Information Criterion (AIC) value. Based on the optimal cutoff value of the ROC curve of the signature, colon cancer patients were divided into the high- and low-risk groups. Then, the signature was evaluated by clinicopathological features, tumor-infiltrating immune cells, checkpoint-related biomarkers, targeted therapy, and chemotherapy.
Results: We identified 8 lncRNA pairs including AC103740.1|LEF1-AS1, LINC02391|AC053503.5, WWC2-AS2|AL355916.2, AC104090.1|NEURL1-AS1, AC099524.1|AL161908.1, AC074011.1|AL078601.2, AL355916.2|LINC01723, and AP003392.4|LINC00598 from 71 differently expressed irlncRNAs. We constructed a prognostic risk score model (a new signature) using these optimal eight irlncRNA pairs. ROC curve analysis revealed that the highest AUC value of the signature was 0.776 at 1 year, with the optimal cutoff value of 1.283. Our present study also showed that the constructed signature could accurately identify adverse survival outcomes, prognostic clinicopathological features, and specify tumor invasion status. The expression of immune checkpoint-related genes and chemical drug sensitivity were related to different risk groups.
Conclusion: In our present study, we constructed a new irlncRNA signature of colon cancer based on the irlncRNA pairs instead of the special expression level of lncRNA. We found this signature had not only good prognostic value but also certain clinical value, which might provide a new insight into the treatment and prognosis of colon cancer.

DOI: https://doi.org/10.1155/2022/5827544
Cancer Med. 2022 Apr 13.

Pan-cancer analysis of mutations in open chromatin regions and their possible association with cancer pathogenesis.

Chie Kikutake, Mikita Suyama.

   BACKGROUND: Open chromatin is associated with gene transcription. Previous studies have shown that the density of mutations in open chromatin regions is lower than that in flanking regions because of the higher accessibility of DNA repair machinery. However, in several cancer types, open chromatin regions show an increased local density of mutations in activated regulatory regions. Although the mutation distribution within open chromatin regions in cancer cells has been investigated, only few studies have focused on their functional implications in cancer. To reveal the impact of highly mutated open chromatin regions on cancer, we investigated the association between mutations in open chromatin regions and their possible functions.
METHODS: Whole-genome sequencing data of 18 cancer types were downloaded from the PanCancer Analysis of Whole Genomes and Catalog of Somatic Mutations in Cancer. We quantified the mutations located in open chromatin regions defined by The Cancer Genome Atlas and classified open chromatin regions into three categories based on the number of mutations. Then, we investigated the chromatin state, amplification, and possible target genes of the open chromatin regions with a high number of mutations. We also analyzed the association between the number of mutations in open chromatin regions and patient prognosis.
RESULTS: In some cancer types, the proportion of promoter or enhancer chromatin state in open chromatin regions with a high number of mutations was significantly higher than that in the regions with a low number of mutations. The possible target genes of open chromatin regions with a high number of mutations were more strongly associated with cancer than those of other open chromatin regions. Moreover, a high number of mutations in open chromatin regions was significantly associated with a poor prognosis in some cancer types.
CONCLUSIONS: These results suggest that highly mutated open chromatin regions play an important role in cancer pathogenesis and can be effectively used to predict patient prognosis.

Keywords:  TCGA; bioinformatics; cancer genetics; genomics; medical genetics

DOI:  https://doi.org/10.1002/cam4.4749
RNA Biol. 2022 Jan;19(1): 533-540

Promoter antisense RNAs: beyond transcription by-products of active promoters.

Fan Yang.

  Omics-based technologies, which have developed rapidly over the last few decades, have generated increasing evidence demonstrating pervasive divergent transcription from RNA polymerase II (Pol II) promoters of eukaryotic genome, and indeed have raised considerable discussion as to their potential physiopathological function. Unlike many other long non-coding RNAs (lncRNAs), promoter antisense RNAs (PAS RNAs) were initially considered to be merely passive transcription by-products of active promoters. However, recent studies have begun to reveal their critical importance in a broad spectrum of biological processes. In this Review, I summarize recent technological advances that enable accurate detection of PAS RNA and discuss the mechanisms of PAS RNA biogenesis emphasizing the functional importance of its structure enabling the diverse functions of PAS RNA in transcription and chromatin regulation.

Keywords:  CRISPR-Cas13; CRISPR-Cas9; Pol II promoter-proximal pause release; Promoter antisense RNA; nascent RNA sequencing

DOI:  https://doi.org/10.1080/15476286.2022.2062177
Front Chem. 2022 ;10 837987

Combining EGFR-TKI With SAHA Overcomes EGFR-TKI-Acquired Resistance by Reducing the Protective Autophagy in Non-Small Cell Lung Cancer.

Peijun Cao, Yongwen Li, Ruifeng Shi, Yin Yuan, Hao Gong, Guangsheng Zhu, Zihe Zhang, Chen Chen, Hongbing Zhang, Minghui Liu, Zhenhua Pan, Hongyu Liu, Jun Chen.

  Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired resistance happens for most patients. In the present research, we found that EGFR-TKIs (such as gefitinib and osimertinib) can induce autophagy in NSCLC cell lines. Compared with parental sensitive cells, drug-resistant cells have higher autophagy activity. The use of an autophagy inhibitor could enhance the toxicity of gefitinib and osimertinib, which indicates that the enhancement of protective autophagy might be one of the mechanisms of EGFR-TKI resistance in NSCLC. In addition, increased autophagy activity is associated with decreased enhancer of zeste homolog 2 (EZH2) expression. Knockdown of EZH2 or EZH2 inhibitor treatment could lead to increased autophagy in NSCLC cells, indicating that EZH2 is a negative regulator of autophagy. We revealed that the increase in autophagy caused by the reduction of EZH2 was reversed in vitro and in vivo when combining gefitinib or osimertinib with suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone deacetylase inhibitor (HDACi). In conclusion, our results indicated that the combination of EGFR-TKIs and SAHA may be a new strategy to overcome EGFR-TKIs acquired resistance.

Keywords:  EGFR-TKI; EGFR-TKI acquired resistance; EZH2; SAHA; autophagy

DOI:  https://doi.org/10.3389/fchem.2022.837987
Eur J Cancer. 2022 Apr 11. pii: S0959-8049(22)00141-1. [Epub ahead of print]168 1-11

Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA.

Iben Lyskjær, Neesha Kara, Solange De Noon, Christopher Davies, Ana Maia Rocha, Anna-Christina Strobl, Inga Usher, Craig Gerrand, Sandra J Strauss, Daniel Schrimpf, Andreas von Deimling, Stephan Beck, Adrienne M Flanagan.

   AIM: Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Circulating free (cfDNA) and circulating tumour DNA (ctDNA) are promising biomarkers for disease surveillance and prognostication in several cancer types; however, few such studies are reported for OS. The purpose of this study was to discover and validate methylation-based biomarkers to detect plasma ctDNA in patients with OS and explore their utility as prognostic markers.
METHODS: Candidate CpG markers were selected through analysis of methylation array data for OS, non-OS tumours and germline samples. Candidates were validated in two independent OS datasets (n = 162, n = 107) and the four top-performing markers were selected. Methylation-specific digital droplet PCR (ddPCR) assays were designed and experimentally validated in OS tumour samples (n = 20) and control plasma samples. Finally, ddPCR assays were applied to pre-operative plasma and where available post-operative plasma from 72 patients with OS, and findings correlated with outcome.
RESULTS: Custom ddPCR assays detected ctDNA in 69% and 40% of pre-operative plasma samples (n = 72), based on thresholds of one or two positive markers respectively. ctDNA was detected in 5/17 (29%) post-operative plasma samples from patients, which in four cases were associated with or preceded disease relapse. Both pre-operative cfDNA levels and ctDNA detection independently correlated with overall survival (p = 0.0015 and p = 0.0096, respectively).
CONCLUSION: Our findings illustrate the potential of mutation-independent methylation-based ctDNA assays for OS. This study lays the foundation for multi-institutional collaborative studies to explore the utility of plasma-derived biomarkers in the management of OS.

Keywords:  Circulating tumour DNA; DNA methylation; Epigenetic biomarkers; Epigenetics; Liquid biopsy; Osteosarcoma; Prognosis

DOI:  https://doi.org/10.1016/j.ejca.2022.03.002
Mol Med. 2022 Apr 14. 28(1): 42

Roles of ARID1A variations in colorectal cancer: a collaborative review.

Shankun Zhao, Weizhou Wu, Zufu Jiang, Fuqin Tang, Lingzhi Ding, Weifang Xu, Libin Ruan.

  Colorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6-66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.

Keywords:  ARID1A variations; Biomarker; Colorectal cancer (CRC); Pathogenesis; Prognosis

DOI:  https://doi.org/10.1186/s10020-022-00469-6
Int J Biol Sci. 2022 ;18(6): 2304-2316

Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis.

Siyuan Chen, Bo Ning, Jinwen Song, Zihan Yang, Li Zhou, Zhiji Chen, Linhong Mao, Hongtao Liu, Qingliang Wang, Song He, Zhihang Zhou.

  Background: Acidic microenvironment is a common physiological phenomenon in tumors, and is closely related to cancer development, but the effects of acidosis on pancreatic adenocarcinoma (PDAC) remains to be elucidated. Methods: Metabonomic assay and transcriptomic microarray were used to detect the changes of metabolites and gene expression profile respectively in acidosis-adapted PDAC cells. Wound healing, transwell and in vivo assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation assays were performed to determine cell proliferation. Results: The acidosis-adapted PDAC cells had stronger metastasis and proliferation ability compared with the control cells. Metabonomic analysis showed that acidosis-adapted PDAC cells had both increased glucose and decreased glycolysis, implying a shift to pentose phosphate pathway. The metabolic shift further led to the inactivation of AMPK by elevating ATP. Transcriptomic analysis revealed that the differentially expressed genes in acidosis-adapted cells were enriched in extracellular matrix modification and Hippo signaling. Besides, MMP1 was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway, but could be reduced by AMPK activator. Conclusion: The present study showed that metabolic reprogramming promotes proliferation and metastasis of acidosis-adapted PDAC cells by inhibiting AMPK/Hippo signaling, thus upregulating MMP1.

Keywords:  AMPK; Acidic microenvironment; Hippo signaling; MMP1; Metastasis; PDAC

DOI:  https://doi.org/10.7150/ijbs.69526