bims-ectoca 2023-06-04 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–06–04
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
Recent advances in the development of peptide-based inhibitors targeting epigenetic readers of histone lysine acetylation and methylation marks.
PRC2 direct transfer from G-quadruplex RNA to dsDNA has implications for RNA-binding chromatin modifiers.
Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.
Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.
Cross-regulation between redox and epigenetic systems in tumorigenesis: molecular mechanisms and clinical applications.
CTDN (Convolutional Temporal Based Deep- Neural Network): An Improvised Stacked Hybrid Computational Approach for Anticancer Drug Response Prediction.

Nature. 2023 May 31.

Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Avishai Gavish, Michael Tyler, Alissa C Greenwald, Rouven Hoefflin, Dor Simkin, Roi Tschernichovsky, Noam Galili Darnell, Einav Somech, Chaya Barbolin, Tomer Antman, Daniel Kovarsky, Thomas Barrett, L Nicolas Gonzalez Castro, Debdatta Halder, Rony Chanoch-Myers, Julie Laffy, Michael Mints, Adi Wider, Rotem Tal, Avishay Spitzer, Toshiro Hara, Maria Raitses-Gurevich, Chani Stossel, Talia Golan, Amit Tirosh, Mario L Suvà, Sidharth V Puram, Itay Tirosh.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

DOI: https://doi.org/10.1038/s41586-023-06130-4
Curr Opin Chem Biol. 2023 May 30. pii: S1367-5931(23)00072-8. [Epub ahead of print]75 102334

Recent advances in the development of peptide-based inhibitors targeting epigenetic readers of histone lysine acetylation and methylation marks.

Sha Liu, Xiang Li, Xin Li, Xiang David Li.

  Inhibitors for epigenetic readers of histone modifications are useful chemical probes to interrogate the functional roles played by their cognate targets in epigenetic regulation and can even serve as drugs for the treatment of diseases associated with the dysregulated targets. However, many epigenetic readers are intractable to small molecules, as the recognition of modified histone peptides commonly involves flat and extended protein surfaces. In contrast, the relatively large sizes and structural complexity of peptides help them achieve tight and specific binding to the target proteins. Increasing efforts have been made to target epigenetic readers using peptide-based inhibitors that can complement small molecules. In this review, we discuss the recent advances in the development of peptide-based inhibitors of lysine acetylation and methylation readers.

Keywords:  Chemical probe; Epigenetic reader; Lysine acetylation; Lysine methylation; Peptide-based inhibitor

DOI:  https://doi.org/10.1016/j.cbpa.2023.102334
Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2220528120

PRC2 direct transfer from G-quadruplex RNA to dsDNA has implications for RNA-binding chromatin modifiers.

Wayne O Hemphill, Regan Fenske, Anne R Gooding, Thomas R Cech.

  The chromatin-modifying enzyme, Polycomb Repressive Complex 2 (PRC2), deposits the H3K27me3 epigenetic mark to negatively regulate expression at numerous target genes, and this activity has been implicated in embryonic development, cell differentiation, and various cancers. A biological role for RNA binding in regulating PRC2 histone methyltransferase activity is generally accepted, but the nature and mechanism of this relationship remains an area of active investigation. Notably, many in vitro studies demonstrate that RNA inhibits PRC2 activity on nucleosomes through mutually antagonistic binding, while some in vivo studies indicate that PRC2's RNA-binding activity is critical for facilitating its biological function(s). Here we use biochemical, biophysical, and computational approaches to interrogate PRC2's RNA and DNA-binding kinetics. Our findings demonstrate that PRC2-polynucleotide dissociation rates are dependent on the concentration of free ligand, indicating the potential for direct transfer between nucleic acid ligands without a free-enzyme intermediate. Direct transfer explains the variation in previously reported dissociation kinetics, allows reconciliation of prior in vitro and in vivo studies, and expands the potential mechanisms of RNA-mediated PRC2 regulation. Moreover, simulations indicate that such a direct transfer mechanism could be obligatory for RNA to recruit proteins to chromatin.

Keywords:  displacement; exchange; methyltransferase; nucleosomes; polynucleotide

DOI:  https://doi.org/10.1073/pnas.2220528120
Adv Sci (Weinh). 2023 Jun 02. e2302228

Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement.

Farnaz Hemmati, Ayuba Akinpelu, Jiyeon Song, Farshad Amiri, Anya McDaniel, Collins McMurray, Alexandros Afthinos, Stelios T Andreadis, Andrew V Aitken, Vinicia C Biancardi, Sharon Gerecht, Panagiotis Mistriotis.

  Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long-term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high-throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement-induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53-mediated cell death. Cumulatively, this work establishes advanced, high-throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

Keywords:  3D confinement; P53; YAP; apoptosis; cell mechanosensing; cell migration

DOI:  https://doi.org/10.1002/advs.202302228
MedComm (2020). 2023 Jun;4(3): e288

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.

Jinze Shen, Qurui Wang, Yunan Mao, Wei Gao, Shiwei Duan.

  Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling-targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor-promoting role by blocking the mitochondria-dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

Keywords:  TRIAP1; apoptosis; cancer biomarker; molecular mechanism; p53; targeted therapy

DOI:  https://doi.org/10.1002/mco2.288
Antioxid Redox Signal. 2023 Jun 02.

Cross-regulation between redox and epigenetic systems in tumorigenesis: molecular mechanisms and clinical applications.

Xiao Zhang, Lifang Ma, Jiayi Wang.

SIGNIFICANCE: Redox and epigenetics are two important regulatory processes of cell physiological functions. The cross-regulation between these processes has critical effects on the occurrence and development of various types of tumors.
RECENT ADVANCES: The core factor that influences redox balance is reactive oxygen species (ROS) generation. ROS functions as a double-edged sword in tumors: low levels of ROS promote tumors, whereas excessive ROS induces various forms of tumor cell death, including apoptosis and ferroptosis as well as necroptosis and pyroptosis. Many studies have shown that the redox balance is influenced by epigenetic mechanisms such as DNA methylation, histone modification, chromatin remodeling, non-coding RNAs (microRNA, long non-coding RNA, and circular RNA), and RNA N6-methyladenosine modification. Several oxidizing or reducing substances also affect the epigenetic state.
CRITICAL ISSUES: In this review, we summarize research on the cross-regulation between redox and epigenetics in cancer and discuss the relevant molecular mechanisms. We also discuss the current research on the clinical applications.
FUTURE DIRECTIONS: Future research can use high-throughput methods to analyze the molecular mechanisms of the cross-regulation between redox and epigenetics using in in vitro and in vivo models in more detail, elucidate regulatory mechanisms, and provide guidance for clinical treatment.

DOI: https://doi.org/10.1089/ars.2023.0253
Comput Biol Chem. 2023 Apr 07. pii: S1476-9271(23)00059-2. [Epub ahead of print]105 107868

CTDN (Convolutional Temporal Based Deep- Neural Network): An Improvised Stacked Hybrid Computational Approach for Anticancer Drug Response Prediction.

Davinder Paul Singh, Baijnath Kaushik.

  The characterization of drug - metabolizing enzymes is a significant problem for customized therapy. It is important to choose the right drugs for cancer victims, and the ability to forecast how those drugs will react is usually based on the available information, genetic sequence, and structural properties. To the finest of our knowledge, this is the first study to evaluate optimization algorithms for selection of features and pharmacogenetics categorization using classification methods based on a successful evolutionary algorithm using datasets from the Cancer Cell Line Encyclopaedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC). The study proposes the uses of Firefly and Grey Wolf Optimization techniques for feature extraction, while comparing the traditional Machine Learning (ML), ensemble ML and Stacking Algorithm with the proposed Convolutional Temporal Deep Neural Network or CTDN. With the potential to increase efficiency from the suggested intelligible classifier model for a suggestive chemotherapeutic drugs response prediction, our study is important in particular for selecting an acceptable feature selection method. The comparison analysis demonstrates that the proposed model not only surpasses the prior state-of-the-art methods, but also uses Grey Wolf and Fire Fly Optimization to lessen multicollinearity and overfitting.

Keywords:  CCLE; CTDN; GDSC; Machine learning and Deep learning algorithms; Stacking

DOI:  https://doi.org/10.1016/j.compbiolchem.2023.107868