bims-ectoca 2022-09-11 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–09–11
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science

The roles of glycolysis in osteosarcoma.
The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response.
Phase separation in epigenetics and cancer stem cells.
Mass Spectrometric-Based Proteomics for Biomarker Discovery in Osteosarcoma: Current Status and Future Direction.
Stochastic population dynamics of cancer stemness and adaptive response to therapies.
Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma.
Histone deacetylation primes self-propagation of heterochromatin domains to promote epigenetic inheritance.
Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis.
Boosting single-cell gene regulatory network reconstruction via bulk-cell transcriptomic data.
EID3 Promotes Cancer Stem Cell-Like Phenotypes in Osteosarcoma through the Activation of PI3K-AKT Signaling Pathway.
Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF-β Induced Osteogenic Target Genes.
Single-cell RNA sequencing reveals intra-tumoral heterogeneity of glioblastoma and a pro-tumor subset of tumor-associated macrophages characterized by EZH2 overexpression.

Front Pharmacol. 2022 ;13 950886

The roles of glycolysis in osteosarcoma.

Zuxi Feng, Yanghuan Ou, Liang Hao.

  Metabolic reprogramming is of great significance in the progression of various cancers and is critical for cancer progression, diagnosis, and treatment. Cellular metabolic pathways mainly include glycolysis, fat metabolism, glutamine decomposition, and oxidative phosphorylation. In cancer cells, reprogramming metabolic pathways is used to meet the massive energy requirement for tumorigenesis and development. Metabolisms are also altered in malignant osteosarcoma (OS) cells. Among reprogrammed metabolisms, alterations in aerobic glycolysis are key to the massive biosynthesis and energy demands of OS cells to sustain their growth and metastasis. Numerous studies have demonstrated that compared to normal cells, glycolysis in OS cells under aerobic conditions is substantially enhanced to promote malignant behaviors such as proliferation, invasion, metastasis, and drug resistance of OS. Glycolysis in OS is closely related to various oncogenes and tumor suppressor genes, and numerous signaling pathways have been reported to be involved in the regulation of glycolysis. In recent years, a vast number of inhibitors and natural products have been discovered to inhibit OS progression by targeting glycolysis-related proteins. These potential inhibitors and natural products may be ideal candidates for the treatment of osteosarcoma following hundreds of preclinical and clinical trials. In this article, we explore key pathways, glycolysis enzymes, non-coding RNAs, inhibitors, and natural products regulating aerobic glycolysis in OS cells to gain a deeper understanding of the relationship between glycolysis and the progression of OS and discover novel therapeutic approaches targeting glycolytic metabolism in OS.

Keywords:  Cancer Progression; glycolysis; key enzymes; osteosarcoma; signaling pathway

DOI:  https://doi.org/10.3389/fphar.2022.950886
Front Immunol. 2022 ;13 971416

The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response.

Ancheng Zheng, Qishan Chen, Li Zhang.

  The Hippo pathway was initially discovered in Drosophila melanogaster and mammals as a key regulator of tissue growth both in physiological and pathological states. Numerous studies depict the vital role of the Hippo pathway in cardiovascular development, heart regeneration, organ size and vascular remodeling through the regulation of YAP (yes-associated protein) translocation. Recently, an increasing number of studies have focused on the Hippo-YAP pathway in inflammation and immunology. Although the Hippo-YAP pathway has been revealed to play controversial roles in different contexts and cell types in the cardiovascular system, the mechanisms regulating tissue inflammation and the immune response remain to be clarified. In this review, we summarize findings from the past decade on the function and mechanism of the Hippo-YAP pathway in CVDs (cardiovascular diseases) such as myocardial infarction, cardiomyopathy and atherosclerosis. In particular, we emphasize the role of the Hippo-YAP pathway in regulating inflammatory cell infiltration and inflammatory cytokine activation.

Keywords:  Hippo-YAP pathway; atherosclerosis; immune; inflammation; myocardial infarction

DOI:  https://doi.org/10.3389/fimmu.2022.971416
Front Oncol. 2022 ;12 922604

Phase separation in epigenetics and cancer stem cells.

Chanchan Xiao, Guangjie Wu, Pengfei Chen, Lijuan Gao, Guobing Chen, Hongyi Zhang.

  Accumulating evidence indicates that liquid-liquid phase separation (LLPS) is the basis of the formation of membrane-less compartments in cells. This biomolecular condensate represented by phase separation may influence epigenetics in cancer stem cells (CSCs), a small subpopulation of cancer cells responding to the initiation, maintenance, metastasis, and therapy resistance of cancer. Understanding the underlying biophysical principles and the specific characteristics of biocondensates would provide insights into the precise blocking of potential tumor targets, thereby fundamentally curbing tumor occurrence, recurrence and metastasis. In this review, we summarized the key phenomenon and experimental detection of phase separation and the possibility of regulating the stemness of CSCs through phase separation. We believe that the mechanism of phase separation in CSCs will open up new avenues for the mystery of tumor formation, and modulating phase separation will be a great strategy for CSC-targeted tumor therapy.

Keywords:  cancer stem cells; epigenetic; liquid-liquid phase separation; phase separation; stemness

DOI:  https://doi.org/10.3389/fonc.2022.922604
Int J Mol Sci. 2022 Aug 28. pii: 9741. [Epub ahead of print]23(17):

Mass Spectrometric-Based Proteomics for Biomarker Discovery in Osteosarcoma: Current Status and Future Direction.

Nutnicha Sirikaew, Dumnoensun Pruksakorn, Parunya Chaiyawat, Somchai Chutipongtanate.

  Due to a lack of novel therapies and biomarkers, the clinical outcomes of osteosarcoma patients have not significantly improved for decades. The advancement of mass spectrometry (MS), peptide quantification, and downstream pathway analysis enables the investigation of protein profiles across a wide range of input materials, from cell culture to long-term archived clinical specimens. This can provide insight into osteosarcoma biology and identify candidate biomarkers for diagnosis, prognosis, and stratification of chemotherapy response. In this review, we provide an overview of proteomics studies of osteosarcoma, indicate potential biomarkers that might be promising therapeutic targets, and discuss the challenges and opportunities of mass spectrometric-based proteomics in future osteosarcoma research.

Keywords:  biomarker; mass-spectrometry; osteogenic sarcoma; proteome; therapeutic target

DOI:  https://doi.org/10.3390/ijms23179741
Essays Biochem. 2022 Sep 08. pii: EBC20220038. [Epub ahead of print]

Stochastic population dynamics of cancer stemness and adaptive response to therapies.

Paras Jain, Atchuta Srinivas Duddu, Mohit Kumar Jolly.

  Intratumoral heterogeneity can exist along multiple axes: Cancer stem cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states, and a spectrum of epithelial-hybrid-mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple stable gene expression patterns ('attractors'). These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.

Keywords:  Cancer Stem Cells; Drug resistance; Intratumoral heterogeneity; Phenotypic plasticity

DOI:  https://doi.org/10.1042/EBC20220038
Front Cell Dev Biol. 2022 ;10 948097

Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma.

Hong Toan Lai, Nataliia Naumova, Antonin Marchais, Nathalie Gaspar, Birgit Geoerger, Catherine Brenner.

  Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.

Keywords:  ADI-PEG20; Metformin; metabolic reprogramming; mitochondria; osteosarcoma; regulated cell death

DOI:  https://doi.org/10.3389/fcell.2022.948097
Nat Struct Mol Biol. 2022 Sep 05.

Histone deacetylation primes self-propagation of heterochromatin domains to promote epigenetic inheritance.

Martin Zofall, Rima Sandhu, Sahana Holla, David Wheeler, Shiv I S Grewal.

Heterochromatin assembly, involving histone H3 lysine-9 methylation (H3K9me), is nucleated at specific genomic sites but can self-propagate across extended domains and, indeed, generations. Self-propagation requires Clr4/Suv39h methyltransferase recruitment by pre-existing H3K9 tri-methylation (H3K9me3) to perpetuate H3K9me deposition and is dramatically affected by chromatin context. However, the mechanism priming self-propagation of heterochromatin remains undefined. We show that robust chromatin association of fission yeast class II histone deacetylase Clr3 is necessary and sufficient to support heterochromatin propagation in different chromosomal contexts. Efficient targeting of Clr3, which suppresses histone turnover and maintains H3K9me3, enables self-propagation of an ectopic heterochromatin domain via the Clr4/Suv39h read-write mechanism requiring methylated histones. The deacetylase activity of Clr3 is necessary and, when inactivated, heterochromatin propagation can be recapitulated by removing two major histone acetyltransferases. Our results show that histone deacetylation, a conserved heterochromatin feature, preserves H3K9me3 that transmits epigenetic memory for stable propagation of silenced chromatin domains through multiple generations.

DOI: https://doi.org/10.1038/s41594-022-00830-7
Life Sci. 2022 Sep 06. pii: S0024-3205(22)00636-1. [Epub ahead of print] 120936

Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis.

Ok-Hyeon Kim, Young Wook Choi, Soon Auck Hong, Mineui Hong, In Ho Chang, Hyun Jung Lee.

   AIMS: Mechanical forces surrounding solid tumors are pervasive in the tumor microenvironment (TME) and abnormally altered as solid tumors progress. Although it has been reported that biomechanical forces, including wall shear stress (WSS), enhance the metastatic features of cancer cells, its mechanism remains unknown. Here, we investigate how cancer cells sense mechanical stress and propagate signals in the TME.
MAIN METHODS: Using a microfluidic device, interstitial fluid-mimicking flow (0.05 dyne cm-2) was applied to the human prostate cancer cell line PC3. Piezo1 siRNA and shRNA lentivirus were applied to PC3 cells to ablate Piezo1 expression. PC3-Luc2 cells expressing control shRNA or shPiezo1 lentivirus were administered into the prostate of BALB/c mice for orthotopic injection.
KEY FINDING: Here, we show that Piezo1, a mechanosensitive ion channel, is activated by WSS in microfluidic channels. Moreover, Yoda1, a Piezo1 agonist, synergistically potentiates cancer cell motility and nuclear retention of YAP/TAZ via WSS. Also, Piezo1 increases Src phosphorylation, which activates YAP. Conversely, silencing Piezo1 significantly reduces cell motility and YAP/TAZ activity induced by WSS, and finally retards tumor growth and metastasis of administered PC3 cells in BALB/c mice.
SIGNIFICANCE: Taken together, these results demonstrate that Piezo1 allows cancer cells to sense mechanical stimuli by altering the microenvironment during tumor progression and is a critical player in modulating cancer metastasis through the Piezo1-Src-YAP axis.

Keywords:  Fluid shear stress; Mechanosensor; Piezo1; Prostate cancer; Src; YAP

DOI:  https://doi.org/10.1016/j.lfs.2022.120936
Brief Bioinform. 2022 Sep 07. pii: bbac389. [Epub ahead of print]

Boosting single-cell gene regulatory network reconstruction via bulk-cell transcriptomic data.

Hantao Shu, Fan Ding, Jingtian Zhou, Yexiang Xue, Dan Zhao, Jianyang Zeng, Jianzhu Ma.

  Computational recovery of gene regulatory network (GRN) has recently undergone a great shift from bulk-cell towards designing algorithms targeting single-cell data. In this work, we investigate whether the widely available bulk-cell data could be leveraged to assist the GRN predictions for single cells. We infer cell-type-specific GRNs from both the single-cell RNA sequencing data and the generic GRN derived from the bulk cells by constructing a weakly supervised learning framework based on the axial transformer. We verify our assumption that the bulk-cell transcriptomic data are a valuable resource, which could improve the prediction of single-cell GRN by conducting extensive experiments. Our GRN-transformer achieves the state-of-the-art prediction accuracy in comparison to existing supervised and unsupervised approaches. In addition, we show that our method can identify important transcription factors and potential regulations for Alzheimer's disease risk genes by using the predicted GRN. Availability: The implementation of GRN-transformer is available at https://github.com/HantaoShu/GRN-Transformer.

Keywords:  gene regulatory network; scRNA-seq; transformer

DOI:  https://doi.org/10.1093/bib/bbac389
Oxid Med Cell Longev. 2022 ;2022 5941562

EID3 Promotes Cancer Stem Cell-Like Phenotypes in Osteosarcoma through the Activation of PI3K-AKT Signaling Pathway.

Yan Wang, Shiyong Luo, Yuxuan Wang, Shengbang Yang, Zhitong Huang, Xuejin Zhu, Shanghua Cai, Qifeng Guo, Weide Zhong, Sihong Liu.

The aim of this study is to elucidate molecular mechanism by which E1A-like inhibitor of differentiation 3 (EID3) promotes cancer stem cell-like phenotypes in osteosarcoma. Overexpression of EID3 in osteosarcoma cells generated more spherical clones, enhanced the expression of stemness-associated genes, and promoted chemoresistance, invasion, and metastasis. Furthermore, osteosarcoma cells overexpressing EID3 had increased ability to grow in suspension as osteospheres with high expression of Sox2 and stem cell marker CD133. In addition, knockdown of EID3 reduced sphere formation and inhibited osteosarcoma cell migration and invasion. RNA sequencing and bioinformatics analysis revealed that PI3K-Akt signaling pathway and MAPK pathway-related genes were enriched in osteosarcoma cells with high expression of EID3. Taken together, EID3 promotes osteosarcoma, and EID3-PI3K-Akt axis is a potential therapeutic target for osteosarcoma treatment.

DOI: https://doi.org/10.1155/2022/5941562
Adv Biol (Weinh). 2021 Feb;5(2): e2000051

Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF-β Induced Osteogenic Target Genes.

Maria Reichenbach, Paul-Lennard Mendez, Carolina da Silva Madaleno, Vladimir Ugorets, Paul Rikeit, Stefan Boerno, Jerome Jatzlau, Petra Knaus.

  Bone is a remarkable dynamic structure, which integrates mechanical and biochemical signaling inputs. Interstitial fluid in the intramedullary space transmits signals derived from compression-induced fluid shear stress (FSS) to stimulate osteoblasts for bone formation. Using a flow system and human osteoblasts, this study demonstrates how BMP/TGF-β signaling integrates stimuli derived from FSS and YAP/TAZ and confirms these findings by transcriptome analyses. Here, FSS positively affects the phosphorylation of both SMAD1/5 and SMAD2/3, the respective BMP- and TGFβ-R-SMADs. Increase in phosphorylated SMAD1/5 levels affects distinct target genes, which are susceptible to low levels of phosphorylated SMADs (such as ID1-3) or dependent on high levels of phosphorylated SMAD1/5 (NOG, noggin). Thus, FSS lowers the threshold for genes dependent on high levels of phosphorylated SMAD1/5 when less BMP is available. While the impact of FSS on direct BMP target genes is independent of YAP/TAZ, FSS acts cooperatively with YAP/TAZ on TGF-β target genes, which are shared by both pathways (such as CTGF). As mechanical stimuli are key in bone regeneration, their crosstalk to biochemical signaling pathways such as BMP and TGF-β and YAP/TAZ acts on different levels, which allows now to think about new and more specified intervention strategies for age-related bone loss.

Keywords:  BMP signaling; TAZ; YAP; fluid shear stress; osteogenic differentiation

DOI:  https://doi.org/10.1002/adbi.202000051
Biochim Biophys Acta Mol Basis Dis. 2022 Aug 31. pii: S0925-4439(22)00205-8. [Epub ahead of print]1868(12): 166534

Single-cell RNA sequencing reveals intra-tumoral heterogeneity of glioblastoma and a pro-tumor subset of tumor-associated macrophages characterized by EZH2 overexpression.

Xiaoyong Chen, Yue Chen, Xiangrong Chen, Penghui Wei, Yuanxiang Lin, Zanyi Wu, Zhangya Lin, Dezhi Kang, Chenyu Ding.

   BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous disease with poor clinical outcome.
AIM: To comprehensively dissect molecular landscape of GBM and heterogeneous distribution and potential role of Enhancer of zeste homolog 2 (EZH2) in tumor microenvironment (TME).
METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was performed in GBM samples from 8 patients. Deconvolution analysis, immunofluorescence (IF) microscopy, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), colony formation experiments, and Cell Counting Kit-8 (CCK-8) assays were performed to confirmed the potential role of EZH2 in TME cells.
RESULTS: Malignant cells exhibited remarkable heterogeneity in abnormal metabolic patterns. A mesenchymal-2-like (MES2-like) GBM subcluster with glial-immune dual feature was firstly discovered, which were associated with highly activated hallmark pathways, immune evasion associated transcription factor (IRF8), and poor survival. The oncogene, EZH2, was heterogeneously expressed in malignant cells and immune cells consistent with proliferative genes, cell-cycle transcription factors, and similar activated hallmark pathways. In a tumor-associated macrophages (TAMs) subset (macrophage.3), EZH2 was highly expressed with similar changes of transcriptomic dynamics with cell-cycle genes and macrophages M2-phetotype genes. In addition, the subset tightly interacted with malignant cells. Deconvolution analysis showed increased abundance of the subset in GBM compared to low-grade glioma (LGG) and significant association with worse prognosis. Functional verification experiments confirmed the pro-tumor role of TAMs with EZH2 overexpression in GBM.
CONCLUSIONS: Our study illustrated a MES2-like GBM subcluster characterized by glial-immune dual feature and highlighted the pro-tumor role of a TAMs subset characterized by EZH2 overexpression.

Keywords:  EZH2; Glioblastoma; Heterogeneity; Macrophage; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.bbadis.2022.166534