bims-ectoca 2022-04-10 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022‒04‒10
twelve papers selected by
Ankita Daiya
BITS Pilani

The Two-Hit Hypothesis Meets Epigenetics.
Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.
Epigenomic alterations in cancer: mechanisms and therapeutic potential.
Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.
HEXOKINASE1 forms a nuclear complex with the PRC2 subunits CURLY LEAF and SWINGER to regulate glucose signaling.
Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?
Epigenetic cell memory: The gene's inner chromatin modification circuit.
Intratumor heterogeneity and anti-tumor immunity shape one another bidirectionally.
RUNX3/H3K27me3 Co-Expression Defines a Better Prognosis in Surgically Resected Stage I and Postoperative Chemotherapy-Naive Non-Small-Cell Lung Cancer.
NEAT1: Culprit lncRNA linking PIG-C, MSLN, and CD80 in triple-negative breast cancer.
Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization.
Testing the reproducibility and robustness of the cancer biology literature by robot.

Cancer Res. 2022 Apr 01. 82(7): 1167-1169

The Two-Hit Hypothesis Meets Epigenetics.

Jean-Pierre Issa.

The landmark paper by Kane and colleagues was the first report of DNA methylation in the promoter of the human MLH1 gene in sporadic colon cancers with mismatch repair (MMR) deficiency. In both cell lines and primary tumors, promoter methylation was associated with loss of MLH1 protein expression and with a lack of mutations in the MLH1 coding region. Together with subsequent papers that showed that this methylation was directly responsible for loss of MLH1 expression and MMR deficiency, the observation expanded the two-hit hypothesis of tumor suppressor gene loss in cancer to include both genetic and epigenetic mechanisms of gene inactivation. More broadly, the paper contributed to normalization of the hypothesis of an epigenetic basis for cancer development. See related article by Kane and colleagues, Cancer Res 1997;57:808-11.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0405
OMICS. 2022 Apr 07.

Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.

Merve Kutay, Devrim Gozuacik, Tunahan Çakır.

  A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular. This work does not include any human subjects. We used data from literature, and they were cell-line data. Therefore, we do not have any IRB or Clinical Registration.

Keywords:  bioinformatics; cancer dormancy; cancer drug discovery; metabolic network models; preventive medicine; transcriptome

DOI:  https://doi.org/10.1089/omi.2022.0008
Clin Sci (Lond). 2022 Apr 14. 136(7): 473-492

Epigenomic alterations in cancer: mechanisms and therapeutic potential.

Jaimie S Gray, Sajad A Wani, Moray J Campbell.

  The human cell requires ways to specify its transcriptome without altering the essential sequence of DNA; this is achieved through mechanisms which govern the epigenetic state of DNA and epitranscriptomic state of RNA. These alterations can be found as modified histone proteins, cytosine DNA methylation, non-coding RNAs, and mRNA modifications, such as N6-methyladenosine (m6A). The different aspects of epigenomic and epitranscriptomic modifications require protein complexes to write, read, and erase these chemical alterations. Reflecting these important roles, many of these reader/writer/eraser proteins are either frequently mutated or differentially expressed in cancer. The disruption of epigenetic regulation in the cell can both contribute to cancer initiation and progression, and increase the likelihood of developing resistance to chemotherapies. Development of therapeutics to target proteins involved in epigenomic/epitranscriptomic modifications has been intensive, but further refinement is necessary to achieve ideal treatment outcomes without too many off-target effects for cancer patients. Therefore, further integration of clinical outcomes combined with large-scale genomic analyses is imperative for furthering understanding of epigenomic mechanisms in cancer.

Keywords:  DNA methylation; epitranscriptomics; histone modifications; lncRNA; m6A; miRNA

DOI:  https://doi.org/10.1042/CS20210449
Front Oncol. 2022 ;12 857686

Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.

Patries M Herst, Georgia M Carson, David A Eccles, Michael V Berridge.

  The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

Keywords:  bioenergetic flexibility; glycolysis-OXPHOS continuum; mito-nuclear gene expression; tumor microenvironment (TME); tumor progression and metastasis

DOI:  https://doi.org/10.3389/fonc.2022.857686
J Integr Plant Biol. 2022 Apr 08.

HEXOKINASE1 forms a nuclear complex with the PRC2 subunits CURLY LEAF and SWINGER to regulate glucose signaling.

Yutong Liu, Yunshu Bai, Ning Li, Mengting Li, Wenxin Liu, Dae-Jin Yun, Bao Liu, Zheng-Yi Xu.

  The glucose sensor HEXOKINASE1 (HXK1) integrates myriad external and internal signals to regulate gene expression and development in Arabidopsis thaliana. However, how HXK1 mediates glucose signaling in the nucleus remains unclear. Here, using immunoprecipitation-coupled mass spectrometry, we show that two catalytic subunits of Polycomb Repressive Complex 2, SWINGER (SWN) and CURLY LEAF (CLF), directly interact with catalytically active HXK1 and its inactive forms (HXK1G104D and HXK1S177A ) via their evolutionarily conserved SANT domains. HXK1, CLF, and SWN target common glucose-responsive genes to regulate glucose signaling, as revealed by RNA-sequencing. The glucose-insensitive phenotypes of the Arabidopsis swn-1 and clf-50 mutants were similar to that of hxk1, and genetic analysis revealed that CLF, SWN, and HXK1 function in the same genetic pathway. Intriguingly, HXK1 is required for CLF- and SWN-mediated H3K27me3 deposition and glucose-mediated gene repression. Moreover, CLF and SWN affect the recruitment of HXK1 to its target chromatin. These findings support a model in which HXK1 and epigenetic modifiers form a nuclear complex to cooperatively mediate glucose signaling, thereby affecting the histone modification and expression of glucose-regulated genes in plants. This article is protected by copyright. All rights reserved.

Keywords:  Arabidopsis thaliana; glucose sensor; hexokinase; histone methylation; transcriptional regulation

DOI:  https://doi.org/10.1111/jipb.13261
Cell Death Differ. 2022 Apr 08.

Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?

Annabella F Thomas, Gemma L Kelly, Andreas Strasser.

The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.

DOI: https://doi.org/10.1038/s41418-022-00996-z
PLoS Comput Biol. 2022 Apr;18(4): e1009961

Epigenetic cell memory: The gene's inner chromatin modification circuit.

Simone Bruno, Ruth J Williams, Domitilla Del Vecchio.

Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit's constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.

DOI: https://doi.org/10.1371/journal.pcbi.1009961
Clin Cancer Res. 2022 Apr 05. pii: clincanres.1355.2021. [Epub ahead of print]

Intratumor heterogeneity and anti-tumor immunity shape one another bidirectionally.

Yochai Wolf, Yardena Samuels.

Over the last decade, it has become clear that the genomic landscapes of tumors profoundly impact their immunogenicity and how tumor cells interact with immune cells. Whereas past discoveries mainly focused on the interplay between tumor immunogenicity and tumor mutational burden (TMB), under the assumption that a higher mutation load would give rise to a better patient response to immune checkpoint blockade (ICB) therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the anti-tumor response and the nature of the tumor microenvironment. In this Review, we define TMB vs. ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex crosstalk between TMB, ITH and anti-tumor immunity in human cancers and in-vivo models, and discuss the mutual influence of ITH and immunity - how the anti-tumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the anti-tumor response.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1355
J Oncol. 2022 ;2022 5752263

RUNX3/H3K27me3 Co-Expression Defines a Better Prognosis in Surgically Resected Stage I and Postoperative Chemotherapy-Naive Non-Small-Cell Lung Cancer.

Xiaohui Chen, Yujie Deng, Chuanzhong Huang, Yi Shi, Jianping Lu, Guibin Weng, Weifeng Zhu, Kunshou Zhu, Junqiang Chen, Jiancheng Li.

The purpose of this study is to investigate the significance of RUNX3/H3K27me3 co-expression in surgically resected non-small-cell lung cancer (NSCLC) patients. Using tissue microarray (TMA), immunohistochemistry, fluorescent double immunostaining, and western blotting, 208 NSCLC and 5 benign pulmonary patients were studied of their expression of runt-related transcription factor 3 (RUNX3), trimethylated histone H3 at lysine 27 (H3K27me3), enhancer of zeste homolog 2 (EZH2), and Ki-67. Apoptotic index in cancerous tissue was evaluated via TdT-mediated dUTP-biotin nick end labeling (TUNEL). The correlation between clinicopathologic parameters and overall survival was determined by Cox regression and Kaplan-Meier survival estimates and log-rank test. GEPIA and KM plotter were used for validation of some survival analyses. As a result, together with other regular prognostic factors, RUNX3/H3K27me3 co-expression was found to be closely correlated with better prognosis in either pTNM-I or POCT-naive NSCLC patients, which might partially result from a higher cancerous apoptotic index. In conclusion, RUNX3/H3K27me3 co-expression defined some specific NSCLC population with better prognosis and longer OS and could probably be used as a biomarker in the prediction of better postoperative outcomes.

DOI: https://doi.org/10.1155/2022/5752263
Life Sci. 2022 Apr 01. pii: S0024-3205(22)00223-5. [Epub ahead of print] 120523

NEAT1: Culprit lncRNA linking PIG-C, MSLN, and CD80 in triple-negative breast cancer.

Nada H Hussein, Reda A Eissa, M de Bruyn, Hend M El Tayebi.

  BACKGROUND: Breast cancer (BC) is the most common cancer in women. Despite the effectiveness of conventional therapies, they cause detrimental side effects. Glycosyl-Phosphatidyl-Inositol (GPI) pathway is a conserved pathway that culminates in the generation of GPI anchored proteins (GPI-AP). Phosphatidyl-Inositol-Glycan Biosynthesis Class C (PIG-C) is the first step in GPI pathway and upon its overexpression, Mesothelin (MSLN); an oncogenic GPI-AP, expression is induced. Therefore, blocking GPI pathway is a potential therapy through which multiple pathways can be rectified. Recombinant GPI-CD80 proved to be a potent immunostimulatory protein and currently being evaluated as tumor vaccine. In fact, CD80 is a unique immunomodulator that binds to CD28, CTLA-4 and PD-L1. Furthermore, research advancement showed that non-coding RNAs (ncRNAs) are key epigenetic modulators. Therefore, epigenetic tuning of GPI-APs remains an unexplored area. This study aims at investigating the potential role of ncRNAs in regulating MSLN, PIG-C and CD80 in BC.METHODS: Potential ncRNAs were filtered by bioinformatics algorithms. MDA-MB-231 cells were transfected with RNA oligonucleotides. Surface CD80 and MSLN were assessed by FACS and immunofluorescence. Gene expression was tested by q-PCR.
RESULTS: PIG-C gene was overexpressed in TNBC and its manipulation altered MSLN surface level. Aligning with bioinformatics analysis, miR-2355 manipulated PIG-C and MSLN expression, while miR-455 manipulated CD80 expression. NEAT1 sponged both miRNAs. Paradoxically, NEAT1 lowered PIG-C gene expression while increased MSLN gene expression.
CONCLUSION: This study unravels novel immunotherapeutic targets for TNBC. NEAT1 is potential immunomodulator by sponging several miRNAs. Finally, this study highlights GPI pathway applications, therefore integrating epigenetics, post-translational modifications and immunomodulation.

Keywords:  CD80; MSLN; NEAT1; PIG-C; TNBC

DOI:  https://doi.org/10.1016/j.lfs.2022.120523
Neoplasia. 2022 Mar 30. pii: S1476-5586(22)00013-6. [Epub ahead of print]27 100784

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization.

Gloria Pedot, Joana Graça Marques, Philip P Ambühl, Marco Wachtel, Stephanie Kasper, Quy A Ngo, Felix K Niggli, Beat W Schäfer.

  Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression.

Keywords:  EWS-FLI1; Ewing sarcoma; Fimepinostat; HDACi; Protein stability

DOI:  https://doi.org/10.1016/j.neo.2022.100784
J R Soc Interface. 2022 Apr;19(189): 20210821

Testing the reproducibility and robustness of the cancer biology literature by robot.

Katherine Roper, A Abdel-Rehim, Sonya Hubbard, Martin Carpenter, Andrey Rzhetsky, Larisa Soldatova, Ross D King.

  Scientific results should not just be 'repeatable' (replicable in the same laboratory under identical conditions), but also 'reproducible' (replicable in other laboratories under similar conditions). Results should also, if possible, be 'robust' (replicable under a wide range of conditions). The reproducibility and robustness of only a small fraction of published biomedical results has been tested; furthermore, when reproducibility is tested, it is often not found. This situation is termed 'the reproducibility crisis', and it is one the most important issues facing biomedicine. This crisis would be solved if it were possible to automate reproducibility testing. Here, we describe the semi-automated testing for reproducibility and robustness of simple statements (propositions) about cancer cell biology automatically extracted from the literature. From 12 260 papers, we automatically extracted statements predicted to describe experimental results regarding a change of gene expression in response to drug treatment in breast cancer, from these we selected 74 statements of high biomedical interest. To test the reproducibility of these statements, two different teams used the laboratory automation system Eve and two breast cancer cell lines (MCF7 and MDA-MB-231). Statistically significant evidence for repeatability was found for 43 statements, and significant evidence for reproducibility/robustness in 22 statements. In two cases, the automation made serendipitous discoveries. The reproduced/robust knowledge provides significant insight into cancer. We conclude that semi-automated reproducibility testing is currently achievable, that it could be scaled up to generate a substantive source of reliable knowledge and that automation has the potential to mitigate the reproducibility crisis.

Keywords:  biology; cancer; literature; reproducibility; robustnesses; testings

DOI:  https://doi.org/10.1098/rsif.2021.0821