bims-ectoca 2023-08-27 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–08–27
eleven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Progress in discovery and development of natural inhibitors of histone deacetylases (HDACs) as anti-cancer agents.
Expressed barcoding enables high resolution tracking of the evolution of drug tolerance.
On the Value of In Vitro Cell Systems for Mechanobiology from the Perspective of Yes-Associated Protein/Transcriptional Co-Activator with a PDZ-Binding Motif and Focal Adhesion Kinase and Their Involvement in Wound Healing, Cancer, Aging, and Senescence.
Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.
Mitochondrial Metabolism: A New Dimension of Personalized Oncology.
The impact of interaction between verteporfin and yes-associated protein 1/transcriptional coactivator with PDZ-binding motif-TEA domain pathway on the progression of isocitrate dehydrogenase wild-type glioblastoma.
Chromatin and non-chromatin immunoprecipitations to capture protein-protein and protein-nucleic acid interactions in living cells.
Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer.
Stochasticity in gene body methylation.
Mechanisms controlling the mechanical properties of the nuclei.
Multi-omics analyses based on genes associated with oxidative stress and phospholipid metabolism revealed the intrinsic molecular characteristics of pancreatic cancer.

Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug 24.

Progress in discovery and development of natural inhibitors of histone deacetylases (HDACs) as anti-cancer agents.

Abhishek Wahi, Priti Jain, Apurba Sinhari, Hemant R Jadhav.

  The study of epigenetic translational modifications had drawn great interest for the last few decades. These processes play a vital role in many diseases and cancer is one of them. Histone acetyltransferase (HAT) and histone deacetylases (HDACs) are key enzymes involved in the acetylation and deacetylation of histones and ultimately in post-translational modifications. Cancer frequently exhibits epigenetic changes, particularly disruption in the expression and activity of HDACs. It includes the capacity to regulate proliferative signalling, circumvent growth inhibitors, escape cell death, enable replicative immortality, promote angiogenesis, stimulate invasion and metastasis, prevent immunological destruction, and genomic instability. The majority of tumours develop and spread as a result of HDAC dysregulation. As a result, HDAC inhibitors (HDACis) were developed, and they today stand as a very promising therapeutic approach. One of the most well-known and efficient therapies for practically all cancer types is chemotherapy. However, the efficiency and safety of treatment are constrained by higher toxicity. The same has been observed with the synthetic HDACi. Natural products, owing to many advantages over synthetic compounds for cancer treatment have always been a choice for therapy. Hence, naturally available molecules are of particular interest for HDAC inhibition and HDAC has drawn the attention of the research fraternity due to their potential to offer a diverse array of chemical structures and bioactive compounds. This diversity opens up new avenues for exploring less toxic HDAC inhibitors to reduce side effects associated with conventional synthetic inhibitors. The review presents comprehensive details on natural product HDACi, their mechanism of action and their biological effects. Moreover, this review provides a brief discussion on the structure activity relationship of selected natural HDAC inhibitors and their analogues which can guide future research to discover selective, more potent HDACi with minimal toxicity.

Keywords:  Cancer; Epigenetic; HDAC inhibitors; Histone acetyltransferase (HAT); Histone deacetylase (HDAC); Natural products; Small molecules

DOI:  https://doi.org/10.1007/s00210-023-02674-4
Cancer Res. 2023 Aug 21. pii: CAN-23-0144. [Epub ahead of print]

Expressed barcoding enables high resolution tracking of the evolution of drug tolerance.

Jennifer L Cotton, Javier Estrada Diez, Vivek Sagar, Julie Chen, Michelle Piquet, John Alford, Youngchul Song, Xiaoyan Li, Markus Riester, Matthew T DiMare, Katja Schumacher, Gaylor Boulay, Kathleen Sprouffske, Lin Fan, Tyler Burks, Leandra Mansur, Joel Wagner, Hyo-Eun C Bhang, Oleg Iartchouk, John Reece-Hoyes, Erick J Morris, Peter S Hammerman, David A Ruddy, Joshua M Korn, Jeffrey A Engelman, Matthew J Niederst.

For a majority of non-small cell lung cancer (NSCLC) patients with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the pre-existing biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi. In this study, we tracked the origins and clonal evolution of drug tolerant cells at a high resolution by using an expressed barcoding system coupled with single cell RNA-sequencing. This platform enabled longitudinally profiling of gene expression and drug sensitivity in response to EGFRi across a large number of clones. Drug tolerant cells had higher expression of key survival pathways such as YAP and EMT at baseline and could also differentially adapt their gene expression following EGFRi treatment compared to sensitive cells. In addition, drug combinations targeting common downstream components (MAPK) or orthogonal factors (chemotherapy) showed greater efficacy than EGFRi alone, which is likely attributable to broader targeting of the multiple EGFRi tolerance mechanisms present in tumors. Overall, this approach facilitates thorough examination of clonal evolution in response to therapy that could inform the development of improved diagnostic approaches and treatment strategies for targeting drug tolerant cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0144
Int J Mol Sci. 2023 Aug 11. pii: 12677. [Epub ahead of print]24(16):

On the Value of In Vitro Cell Systems for Mechanobiology from the Perspective of Yes-Associated Protein/Transcriptional Co-Activator with a PDZ-Binding Motif and Focal Adhesion Kinase and Their Involvement in Wound Healing, Cancer, Aging, and Senescence.

Thorsten Steinberg, Martin Philipp Dieterle, Imke Ramminger, Charlotte Klein, Julie Brossette, Ayman Husari, Pascal Tomakidi.

  Mechanobiology comprises how cells perceive different mechanical stimuli and integrate them into a process called mechanotransduction; therefore, the related mechanosignaling cascades are generally important for biomedical research. The ongoing discovery of key molecules and the subsequent elucidation of their roles in mechanobiology are fundamental to understanding cell responses and tissue conditions, such as homeostasis, aging, senescence, wound healing, and cancer. Regarding the available literature on these topics, it becomes abundantly clear that in vitro cell systems from different species and tissues have been and are extremely valuable tools for enabling the discovery and functional elucidation of key mechanobiological players. Therefore, this review aims to discuss the significant contributions of in vitro cell systems to the identification and characterization of three such key players using the selected examples of yes-associated protein (YAP), its paralog transcriptional co-activator with a PDZ-binding motif (TAZ), and focal adhesion kinase (FAK) and their involvement in wound healing, cancer, aging, and senescence. In addition, the reader is given suggestions as to which future prospects emerge from the in vitro studies discussed herein and which research questions still remain open.

Keywords:  aging; cancer; focal adhesion kinase; in vitro cell system(s); mechanobiology; mechanosignaling; mechanotransduction; senescence; tissue homeostasis; wound healing; yes-associated protein

DOI:  https://doi.org/10.3390/ijms241612677
J Cancer Res Clin Oncol. 2023 Aug 22.

Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

Hewen Shi, Ying Zou, Weiwei Zhong, Zhaoying Li, Xiaoxue Wang, Yancun Yin, Defang Li, Ying Liu, Minjing Li.

   BACKGROUND: The Hippo signaling pathway is an evolutionarily conserved signaling module that controls organ size in different species, and the disorder of the Hippo pathway can induce liver cancer in organisms, especially hepatocellular carcinoma (HCC). The exact mechanism that causes cancer is still unknown. Recent studies have shown that it is a classical kinase cascade that phosphorylates the Mst1/2-sav1 complex and activates the phosphorylation of the Lats1/2-mob1A/B complex for inactivating Yap and Taz. These kinases and scaffolds are regarded as primary regulators of the Hippo pathway, and help in activating a variety of carcinogenic processes. Among them, Yap/Taz is seen to be the main effector molecule, which is downstream of the Hippo pathway, and its abnormal activation is related to a variety of human cancers including liver cancer. Currently, since Yap/Taz plays a variety of roles in cancer promotion and tumor regeneration, the Hippo pathway has emerged as an attractive target in recent drug development research.
METHODS: We collect and review relevant literature in web of Science and Pubmed.
CONCLUSION: This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

Keywords:  Hepatocellular carcinoma; Hippo pathway; Signal transduction; YAP/TAZ

DOI:  https://doi.org/10.1007/s00432-023-05272-2
Cancers (Basel). 2023 Aug 11. pii: 4058. [Epub ahead of print]15(16):

Mitochondrial Metabolism: A New Dimension of Personalized Oncology.

Babak Behnam, Farzad Taghizadeh-Hesary.

  Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells' biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironments, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The tumors' responses to anticancer treatments vary, ranging from a complete response to even cancer progression during treatment. Therefore, personalized cancer treatment is of crucial importance. So far, personalized cancer treatment has been based on genomic analysis. Evidence shows that tumors with high mitochondrial content are more resistant to treatment. This paper illustrates how mitochondrial metabolism can participate in cancer resistance to chemotherapy, immunotherapy, and radiotherapy. Pretreatment evaluation of mitochondrial metabolism can provide additional information to genomic analysis and can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.

Keywords:  T cell; cancer stem cell; mitochondria; personalized oncology

DOI:  https://doi.org/10.3390/cancers15164058
J Cent Nerv Syst Dis. 2023 ;15 11795735231195760

The impact of interaction between verteporfin and yes-associated protein 1/transcriptional coactivator with PDZ-binding motif-TEA domain pathway on the progression of isocitrate dehydrogenase wild-type glioblastoma.

Mahmoud Osama, Muhammed Amir Essibayi, Mona Osama, Ismail A Ibrahim, Mostafa Nasr Mostafa, Murat Şakir Ekşi.

  Verteporfin and 5-ALA are used for visualizing malignant tissue components in different body tumors and as photodynamic therapy in treating isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM). Additionally, verteporfin interferes with Yes-associated protein 1 (YAP)/Transcriptional coactivator with PDZ-binding motif - TEA domain (TAZ-TEAD) pathway, thus inhibiting the downstream effect of these oncogenes and reducing the malignant properties of GBM. Animal studies have shown verteporfin to be successful in increasing survival rates, which have led to the conduction of phase 1 and 2 clinical trials to further investigate its efficacy in treating GBM. In this article, we aimed to review the novel mechanism of verteporfin's action, the impact of its interaction with YAP/TAZ-TEAD, its effect on glioblastoma stem cells, and its role in inducing ferroptosis.

Keywords:  Glioblastoma; YAP/TAZ-TEAD pathway; ferroptosis; glioblastoma stem cells; verteporfin

DOI:  https://doi.org/10.1177/11795735231195760
Methods. 2023 Aug 21. pii: S1046-2023(23)00142-1. [Epub ahead of print]

Chromatin and non-chromatin immunoprecipitations to capture protein-protein and protein-nucleic acid interactions in living cells.

Priyanka Barman, Amala Kaja, Pritam Chakraborty, Sukesh R Bhaumik.

  Proteins are expressed from genes via sequential biological processes of transcription, mRNA processing, export and translation, and play their roles in maintaining cellular functions via interactions with proteins, DNAs or RNAs. Thus, it is important to study the protein interactions during biological processes in living cells towards understanding their mechanisms-of-action in real time. Methodologies have been developed over the years to study protein interactions in vivo. One state-of-the-art approach is formaldehyde crosslinking-based immuno- or chemi-precipitation to analyze selective as well as genome/proteome-wide interactions in living cells. It is a popular and widely used methodology for cellular analysis of the protein-protein and protein-nucleic acid interactions. Here, we describe this approach to analyze protein-protein/nucleic acid interactions in vivo.

Keywords:  And chromatin fractionation; Chromatin immunoprecipitation; Formaldehyde-based crosslinking; Immunoprecipitation; RNA immunoprecipitation

DOI:  https://doi.org/10.1016/j.ymeth.2023.08.013
Cell Rep Med. 2023 Aug 10. pii: S2666-3791(23)00315-4. [Epub ahead of print] 101162

Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer.

Yunguang Li, Shijie Tang, Xiaohan Shi, Jingwen Lv, Xueyuan Wu, Yehan Zhang, Huan Wang, Juan He, Yiqin Zhu, Yi Ju, Yajuan Zhang, Shiwei Guo, Weiwei Yang, Huiyong Yin, Luonan Chen, Dong Gao, Gang Jin.

Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.

DOI: https://doi.org/10.1016/j.xcrm.2023.101162
Curr Opin Plant Biol. 2023 Aug 17. pii: S1369-5266(23)00101-2. [Epub ahead of print]75 102436

Stochasticity in gene body methylation.

Constantin Goeldel, Frank Johannes.

  Gene body methylation (gbM) is a widely conserved epigenetic feature of plant genomes. Efforts to delineate the mechanisms by which gbM contributes to transcriptional regulation remain largely inconclusive, and its evolutionary significance continues to be debated. Curiously, although steady-state gbM levels are remarkably stable across mitotic and meiotic cell divisions, the methylation status of individual CG dinucleotides in gbM genes is highly stochastic. How can these two seemingly contradictory observations be reconciled? Here, we discuss how stochastic processes relate to gbM maintenance dynamics. We show that a quantitative understanding of these processes can shed deeper insights into the molecular and evolutionary biology of this enigmatic epigenetic trait.

Keywords:  CMT3; DNA methylation; Epimutation rate; Epimutations; Evolution; Gene body methylation; H2A.Z; MET1; Modeling; Steady state

DOI:  https://doi.org/10.1016/j.pbi.2023.102436
Curr Opin Cell Biol. 2023 Aug 22. pii: S0955-0674(23)00071-6. [Epub ahead of print]84 102222

Mechanisms controlling the mechanical properties of the nuclei.

Giulia Bastianello, Marco Foiani.

The mechanical properties of the nucleus influence different cellular and nuclear functions and have relevant implications for several human diseases. The nucleus protects genetic information while acting as a mechano-sensory hub in response to internal and external forces. Cells have evolved mechano-transduction signaling to respond to physical cellular and nuclear perturbations and adopted a multitude of molecular pathways to maintain nuclear shape stability and prevent morphological abnormalities of the nucleus. Here we describe those key biological processes that control nuclear mechanics and discuss emerging perspectives on the mechanobiology of the nucleus as a diagnostic tool and clinical target.

DOI: https://doi.org/10.1016/j.ceb.2023.102222
Sci Rep. 2023 Aug 21. 13(1): 13564

Multi-omics analyses based on genes associated with oxidative stress and phospholipid metabolism revealed the intrinsic molecular characteristics of pancreatic cancer.

Hongdong Wang, Hui Guo, Jiaao Sun, Yuefeng Wang.

Oxidative stress (OS), which impacts lipid metabolic reprogramming, can affect the biological activities of cancer cells. How oxidative stress and phospholipid metabolism (OSPM) influence the prognosis of pancreatic cancer (PC) needs to be elucidated. The metabolic data of 35 pancreatic tumor samples, 34 para-carcinoma samples, and 31 normal pancreatic tissues were obtained from the previously published literature. Pan-cancer samples were obtained from The Cancer Genome Atlas (TCGA). And the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), ArrayExpress, and the Genotype-Tissue Expression (GTEx) databases were searched for more PC and normal pancreatic samples. The metabolites in PC were compared with normal and para-carcinoma tissues. The characteristics of the key OSPM genes were summarized in pan-cancer. The random survival forest analysis and multivariate Cox regression analysis were utilized to construct an OSPM-related signature. Based on this signature, PC samples were divided into high- and low-risk subgroups. The dysregulations of the tumor immune microenvironment were further investigated. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to investigate the expression of genes in the signature in PC and normal tissues. The protein levels of these genes were further demonstrated. In PC, metabolomic studies revealed the alteration of PM, while transcriptomic studies showed different expressions of OSPM-related genes. Then 930 PC samples were divided into three subtypes with different prognoses, and an OSPM-related signature including eight OSPM-related genes (i.e., SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, ECT2, SLC22A3, and FGD6) was developed. High- and low-risk subgroups divided by the signature showed different prognoses, expression levels of immune checkpoint genes, immune cell infiltration, and tumor microenvironment. The risk score was negatively correlated with the proportion of TIL, pDC, Mast cell, and T cell co-stimulation. The expression levels of genes in the signature were verified in PC and normal samples. The protein levels of SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, and SLC22A3 showed up-regulation in PC samples compared with normal tissues. After integrating metabolomics and transcriptomics data, the alterations in OSPM in PC were investigated, and an OSPM-related signature was developed, which was helpful for the prognostic assessment and individualized treatment for PC.

DOI: https://doi.org/10.1038/s41598-023-40560-4