bims-ectoca 2023-04-30 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–04–30
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.
Leveraging Hot Spots of TEAD-Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling.
Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors.
A patent review of EZH2 inhibitors from 2017 and beyond.
Osteosarcoma tumors maintain intra-tumoral transcriptional heterogeneity during bone and lung colonization.
Deciphering cell-cell interactions and communication in the tumor microenvironment and unraveling intratumoral genetic heterogeneity via single-cell genomic sequencing.
Statistical inference of the rates of cell proliferation and phenotypic switching in cancer.
Identification and functional comparison of novel alternatively spliced isoforms of human YAP.

PLoS Biol. 2023 Apr;21(4): e3002081

Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.

Jonathan B Coulter, Hariharan Easwaran.

Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.

DOI: https://doi.org/10.1371/journal.pbio.3002081
Pharmaceuticals (Basel). 2023 Apr 13. pii: 583. [Epub ahead of print]16(4):

Leveraging Hot Spots of TEAD-Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling.

Bin Zhao, Ajaybabu V Pobbati, Brian P Rubin, Shaun Stauffer.

  The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP-TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP-TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer.

Keywords:  Hippo pathway; TEAD; VGLL; YAP; protein-protein interaction; transcription

DOI:  https://doi.org/10.3390/ph16040583
Ann Med. 2023 Dec;55(1): 2203946

Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors.

Moustafa M Madkour, Wafaa S Ramadan, Ekram Saleh, Raafat El-Awady.

   INTRODUCTION: Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues.
AREAS COVERED: This review highlights the evidence available till date on the influence of different epigenetic modifications on the response to Top I inhibitors as well as the implications of targeting epigenetic alterations for improving the efficacy and safety of Top I inhibitors.
EXPERT OPINION: The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.

Keywords:  Cancer; DNA methylation; Top I; Top I inhibitors; epigenetic; histone modifications; noncoding RNAs; resistance

DOI:  https://doi.org/10.1080/07853890.2023.2203946
Expert Opin Ther Pat. 2023 Apr 24.

A patent review of EZH2 inhibitors from 2017 and beyond.

Guoquan Wan, Huan Feng, Chang Su, Yongxia Zhu, Lidan Zhang, Qiangsheng Zhang, Luoting Yu.

   INTRODUCTION: EZH2 is an important epigenetic regulator that forms the PRC2 complex with SUZ12, EED and RbAp46/48. As the key catalytic subunit of PRC2, EZH2 regulates the trimethylation of histone H3K27, which in turn promotes chromatin condensation and represses the transcription of relevant target genes. EZH2 overexpression and mutations are strictly related to tumor proliferation, invasion and metastasis. Currently, a large number of highly specific EZH2 inhibitors have been developed and some have already been in clinical trials.
AREAS COVERED: The aim of the present review is to provide an overview of the molecular mechanisms of EZH2 inhibitors and to highlight the research advances in the patent literature published from 2017 to date. A search of the literature and patents for EZH2 inhibitors and degraders was performed using the Web of Science, SCIFinder, WIPO, USPTO, EPO and CNIPA databases.
EXPERT OPINION: In recent years, a great number of structurally diverse EZH2 inhibitors have been identified, including EZH2 reversible inhibitors, EZH2 irreversible inhibitors, EZH2-based dual inhibitors and EZH2 degraders. Despite the multiple challenges, EZH2 inhibitors offer promising potential for the treatment of various diseases, such as cancers.

Keywords:  Cancer; Degrader; EZH2 inhibitor; Patent; Tazemetostat

DOI:  https://doi.org/10.1080/13543776.2023.2206018
BMC Biol. 2023 Apr 27. 21(1): 98

Osteosarcoma tumors maintain intra-tumoral transcriptional heterogeneity during bone and lung colonization.

Sanjana Rajan, Emily M Franz, Camille A McAloney, Tatyana A Vetter, Maren Cam, Amy C Gross, Cenny Taslim, Meng Wang, Matthew V Cannon, Alexander Oles, Ryan D Roberts.

   BACKGROUND: Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms-it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies.
RESULTS: We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations.
CONCLUSIONS: Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures.

Keywords:  Clonal selection; Heterogeneity; Metastasis; Microenvironment; Osteosarcoma; Transcriptional profile

DOI:  https://doi.org/10.1186/s12915-023-01593-3
Bioengineered. 2022 Jul-Dec;13(7-12):13(7-12): 14974-14986

Deciphering cell-cell interactions and communication in the tumor microenvironment and unraveling intratumoral genetic heterogeneity via single-cell genomic sequencing.

Ya-Hong Cao, Jie Ding, Qing-Hai Tang, Jie Zhang, Zhong-Yan Huang, Xiao-Mei Tang, Ji-Bin Liu, Yu-Shui Ma, Da Fu.

  A tumor's heterogeneity has important implications in terms of its clonal origin, progression, stemness, and drug resistance. Therefore, because of its significance in treatment, it is important to understand the gene expression pattern of a single cell, track gene expression or mutation in heterogeneous cells, evaluate the clonal origin of cancer cells, and determine the selective evolution of different subpopulations of cancer cells. Researchers are able to trace a cell's mutation and identify different types of tumor cells by measuring the whole transcriptome with single-cell sequencing (scRNA-seq). This technology provides a better understanding of the molecular mechanisms driving tumor growth than that offered by traditional RNA sequencing methods. In addition, it has revealed changes in the mutations and functions of somatic cells as a tumor evolves; it has also clarified immune cell infiltration and activation. Research on scRNA-seq technology has recently advanced significantly, suggesting new strategies for the treatment of cancer. In short, cancer researchers have become increasingly dependent on scRNA-seq. This paper reviews the development, detection principles, and processes of scRNA-seq technology and their application in tumor research. It also considers potential clinical applications.

Keywords:  ScRNA-seq; TME; cell-cell interactions; genome evolution; heterogeneity

DOI:  https://doi.org/10.1080/21655979.2023.2185434
J Theor Biol. 2023 Apr 20. pii: S0022-5193(23)00093-0. [Epub ahead of print] 111497

Statistical inference of the rates of cell proliferation and phenotypic switching in cancer.

Einar Bjarki Gunnarsson, Jasmine Foo, Kevin Leder.

  Recent evidence suggests that nongenetic (epigenetic) mechanisms play an important role at all stages of cancer evolution. In many cancers, these mechanisms have been observed to induce dynamic switching between two or more cell states, which commonly show differential responses to drug treatments. To understand how these cancers evolve over time, and how they respond to treatment, we need to understand the state-dependent rates of cell proliferation and phenotypic switching. In this work, we propose a rigorous statistical framework for estimating these parameters, using data from commonly performed cell line experiments, where phenotypes are sorted and expanded in culture. The framework explicitly models the stochastic dynamics of cell division, cell death and phenotypic switching, and it provides likelihood-based confidence intervals for the model parameters. The input data can be either the fraction of cells or the number of cells in each state at one or more time points. Through a combination of theoretical analysis and numerical simulations, we show that when cell fraction data is used, the rates of switching may be the only parameters that can be estimated accurately. On the other hand, using cell number data enables accurate estimation of the net division rate for each phenotype, and it can even enable estimation of the state-dependent rates of cell division and cell death. We conclude by applying our framework to a publicly available dataset.

Keywords:  Cancer evolution; Epigenetics; Mathematical modeling; Maximum likelihood estimation; Parameter identifiability; Phenotypic switching

DOI:  https://doi.org/10.1016/j.jtbi.2023.111497
FEBS Open Bio. 2023 Apr 26.

Identification and functional comparison of novel alternatively spliced isoforms of human YAP.

Lianlian Liu, Junlei Zhang, Jiaqi Wang, Yanping Tian, Jiali Wang, Yixiao Xu, Yuda Cheng, Meng Yu, Jiangjun Wang, Yi Yang, Xueyue Wang, Ran Yang, Wei Wu, Chen Zhang, Yan Hu, Rui Jian, Lan Xiao, Yan Ruan.

  As a key effector of the Hippo pathway, Yes-associated protein (YAP) is a major regulator of cell proliferation and apoptosis. In this study, 23 hYAP isoforms were identified in HEK293 cells, with 14 isoforms being reported for the first time. These isoforms were classified into hYAP-a and hYAP-b isoforms based on the variation in exon 1. The two groups of isoforms showed distinctly different subcellular localizations. hYAP-a isoforms could activate TEAD- or P73-mediated transcription, affect the proliferation rate and enhance the cellular chemosensitivity of HEK293 cells. Moreover, different activation abilities and pro-cytotoxic effects were observed among hYAP-a isoforms. However, hYAP-b isoforms were not found to exert any significant biological effects. Our findings add to the knowledge of YAP gene structure and protein-coding capacity and will help in the elucidation of the function and related molecular mechanisms of the Hippo-YAP signaling pathway.

Keywords:  YAP; alternative splicing; cell chemosensitivity; transcriptional activation ability

DOI:  https://doi.org/10.1002/2211-5463.13618