bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021‒10‒10
fourteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy.
  2. Fluorescent molecular probe-based activity and inhibition monitoring of histone deacetylases.
  3. PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency.
  4. In-Silico Analysis of Chromatin Modifiers and Profiling of Histone Deacetylases (HDAC's) in Human Oral Cancer.
  5. Polycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction.
  6. Improved detection of tumor suppressor events in single-cell RNA-Seq data.
  7. Cancer microcell initiation and determination.
  8. The SWI/SNF complex, transcription-replication conflicts and cancer: a connection with high therapeutic potential.
  9. Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms.
  10. Chemical Biology Toolbox to Visualize Protein Aggregation in Live Cells.
  11. TRIM59 promotes osteosarcoma progression via activation of STAT3.
  12. Polycomb group proteins in cancer: multifaceted functions and strategies for modulation.
  13. Evolving cancer-niche interactions and therapeutic targets during bone metastasis.
  14. DeepCellState: An autoencoder-based framework for predicting cell type specific transcriptional states induced by drug treatment.
  1. Front Pharmacol. 2021 ;12 702360
    Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy.
    Wenjing Xiao, Qiaodan Zhou, Xudong Wen, Rui Wang, Ruijie Liu, Tingting Wang, Jianyou Shi, Yonghe Hu, Jun Hou.
      Cancer treatment is a significant challenge for the global health system, although various pharmacological and therapeutic discoveries have been made. It has been widely established that cancer is associated with epigenetic modification, which is reversible and becomes an attractive target for drug development. Adding chemical groups to the DNA backbone and modifying histone proteins impart distinct characteristics on chromatin architecture. This process is mediated by various enzymes modifying chromatin structures to achieve the diversity of epigenetic space and the intricacy in gene expression files. After decades of effort, epigenetic modification has represented the hallmarks of different cancer types, and the enzymes involved in this process have provided novel targets for antitumor therapy development. Epigenetic drugs show significant effects on both preclinical and clinical studies in which the target development and research offer a promising direction for cancer therapy. Here, we summarize the different types of epigenetic enzymes which target corresponding protein domains, emphasize DNA methylation, histone modifications, and microRNA-mediated cooperation with epigenetic modification, and highlight recent achievements in developing targets for epigenetic inhibitor therapy. This article reviews current anticancer small-molecule inhibitors targeting epigenetic modified enzymes and displays their performances in different stages of clinical trials. Future studies are further needed to address their off-target effects and cytotoxicity to improve their clinical translation.
    Keywords:  cancer biomarker; epigenetic drugs; epigenetic reprogramming; histone modification; microRNA; small-molecule inhibitors
    DOI:  https://doi.org/10.3389/fphar.2021.702360
  2. Chem Commun (Camb). 2021 Oct 06.
    Fluorescent molecular probe-based activity and inhibition monitoring of histone deacetylases.
    Roopa, Bhanu Priya, Vandana Bhalla, Manoj Kumar, Naresh Kumar.
      Extensive studies in recent decades have revealed that gene expression regulation is not limited to genetic mutations but also to processes that do not alter the genetic sequence. Post-translational histone modification is one of these processes in addition to DNA or RNA modifications. Histone modifications are essential in controlling histone functions and play a vital role in cellular gene expression. The reversible histone acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is an example of such modifications. HDACs are involved in the deacetylation of histones and lead to the termination of gene expression. Although this cellular process is essential, upregulation of HDACs is found in numerous cancers. Therefore, research related to the activity and inhibition monitoring of HDACs is necessary to gain profound knowledge of these enzymes and evaluate the success of the therapeutic approach. In this perspective, methodology derived from fluorescent molecular probes is one of the preferable methods. Herein, we describe fluorescent probes developed to target HDACs by considering their activity and inhibition characteristics.
    DOI:  https://doi.org/10.1039/d1cc04034k
  3. Nat Struct Mol Biol. 2021 Oct;28(10): 811-824
    PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency.
    Paula Dobrinić, Aleksander T Szczurek, Robert J Klose.
      The Polycomb repressive system plays a fundamental role in controlling gene expression during mammalian development. To achieve this, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) bind target genes and use histone modification-dependent feedback mechanisms to form Polycomb chromatin domains and repress transcription. The inter-relatedness of PRC1 and PRC2 activity at these sites has made it difficult to discover the specific components of Polycomb chromatin domains that drive gene repression and to understand mechanistically how this is achieved. Here, by exploiting rapid degron-based approaches and time-resolved genomics, we kinetically dissect Polycomb-mediated repression and discover that PRC1 functions independently of PRC2 to counteract RNA polymerase II binding and transcription initiation. Using single-cell gene expression analysis, we reveal that PRC1 acts uniformly within the cell population and that repression is achieved by controlling transcriptional burst frequency. These important new discoveries provide a mechanistic and conceptual framework for Polycomb-dependent transcriptional control.
    DOI:  https://doi.org/10.1038/s41594-021-00661-y
  4. Chonnam Med J. 2021 Sep;57(3): 176-184
    In-Silico Analysis of Chromatin Modifiers and Profiling of Histone Deacetylases (HDAC's) in Human Oral Cancer.
    Anand K Sajnani, Sanket G Shah, Mudasir Rashid, Abhiram Natu, Poonam B Gera, Sanjay Gupta.
      Histone modifications have been demonstrated to play a significant role in oral squamous cell carcinoma (OSCC) epigenetic regulation. An in-silico analysis of The Cancer Genome Atlas (TCGA) of various histone acetyl transferases (HATs) and histone deacetylases (HDACs) suggested that HATs do not differ between normal and tumor samples whereas HDAC2 and HDAC1 change maximally and marginally respectively between normal and tumor patients with no change being noted in HDAC6 expression. Hence, this investigation was carried out to validate the expression states of HDAC 1, 2 and 6 mRNAs in buccal mucosa and tongue SCC samples in an Indian cohort. Buccal mucosa and tongue squamous cell carcinoma tissues with intact histopathology were processed for RNA isolation followed by cDNA synthesis which was then subjected to q-PCR for HDACs. The average RNA yield of the tongue tissue sample was ∼2 µg/mg of tissue and the A260/280 ratios were between 2.03 and 2.06. The average RNA yield of buccal mucosa tissue sample was ∼1 µg/mg of tissue and the A260/280 ratio were between 2.00 and 2.08. We have demonstrated that HDAC2 was overexpressed in tongue and buccal mucosa samples. Over-expression of HDAC2 imply potential use of HDACi along with standard chemotherapeutic drug in oral cancer treatment.
    Keywords:  Histone Acetylases; Histone Deacetylases; Oral Squamous Cell Carcinoma
    DOI:  https://doi.org/10.4068/cmj.2021.57.3.176
  5. Nat Commun. 2021 Oct 07. 12(1): 5888
    Polycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction.
    Jorine M Eeftens, Manya Kapoor, Davide Michieletto, Clifford P Brangwynne.
      Organization of the genome into transcriptionally active euchromatin and silenced heterochromatin is essential for eukaryotic cell function. Phase-separation has been implicated in heterochromatin formation, but it is unclear how phase-separated condensates can contribute to stable repression, particularly for heritable epigenetic changes. Polycomb complex PRC1 is key for heterochromatin formation, but the multitude of Polycomb proteins has hindered our understanding of their collective contribution to chromatin repression. Here, we show that PRC1 forms multicomponent condensates through hetero-oligomerization. They preferentially seed at H3K27me3 marks, and subsequently write H2AK119Ub marks. We show that inducing Polycomb phase-separation can cause chromatin compaction, but polycomb condensates are dispensable for maintenance of the compacted state. Our data and simulations are consistent with a model in which the time integral of Polycomb phase-separation is progressively recorded in repressive histone marks, which subsequently drive compaction. These findings link the equilibrium thermodynamics of phase-separation with the fundamentally non-equilibrium concept of epigenetic memory.
    DOI:  https://doi.org/10.1038/s41467-021-26147-5
  6. NPJ Genom Med. 2020 Oct 07. 5(1): 43
    Improved detection of tumor suppressor events in single-cell RNA-Seq data.
    Andrew E Teschendorff, Ning Wang.
      Tissue-specific transcription factors are frequently inactivated in cancer. To fully dissect the heterogeneity of such tumor suppressor events requires single-cell resolution, yet this is challenging because of the high dropout rate. Here we propose a simple yet effective computational strategy called SCIRA to infer regulatory activity of tissue-specific transcription factors at single-cell resolution and use this tool to identify tumor suppressor events in single-cell RNA-Seq cancer studies. We demonstrate that tissue-specific transcription factors are preferentially inactivated in the corresponding cancer cells, suggesting that these are driver events. For many known or suspected tumor suppressors, SCIRA predicts inactivation in single cancer cells where differential expression does not, indicating that SCIRA improves the sensitivity to detect changes in regulatory activity. We identify NKX2-1 and TBX4 inactivation as early tumor suppressor events in normal non-ciliated lung epithelial cells from smokers. In summary, SCIRA can help chart the heterogeneity of tumor suppressor events at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41525-020-00151-y
  7. BMC Cancer. 2021 Oct 08. 21(1): 1087
    Cancer microcell initiation and determination.
    Zane Simsone, Tālivaldis Freivalds, Dina Bēma, Indra Miķelsone, Liene Patetko, Juris Bērziņš, Līga Harju, Indulis Buiķis.
      BACKGROUND: Cancer remains one of the leading causes of death worldwide, despite the possibilities to detect early onset of the most common cancer types. The search for the optimal therapy is complicated by the cancer diversity within tumors and the unsynchronized development of cancerous cells. Therefore, it is necessary to characterize cancer cell populations after treatment has been applied, because cancer recurrence is not rare. In our research, we concentrated on small cancer cell subpopulation (microcells) that has a potential to be cancer resistance source. Previously made experiments has shown that these cells in small numbers form in specific circumstances after anticancer treatment.METHODS: In experiments described in this research, the anticancer agents' paclitaxel and doxorubicin were used to stimulate the induction of microcells in fibroblast, cervix adenocarcinoma, and melanoma cell lines. Mainly for the formation of microcells in melanoma cells. The drug-stimulated cells were then characterized in terms of their formation efficiency, morphology, and metabolic activity.
    RESULTS: We observed the development of cancer microcells and green fluorescent protein (GFP) transfection efficiency after stress. In the time-lapse experiment, we observed microcell formation through a renewal process and GFP expression in the microcells. Additionally, the microcells were viable after anticancer treatment, as indicated by the nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) enzyme activity assay results. Taken together, these findings indicate that cancer microcells are viable and capable of resisting the stress induced by anticancer drugs, and these cells are prone to chemical substance uptake from the environment.
    CONCLUSION: Microcells are not only common to a specific cancer type, but can be found in any tumor type. This study could help to understand cancer emergence and recurrence. The appearance of microcells in the studied cancer cell population could be an indicator of the individual anticancer therapy effectiveness and patient survival.
    Keywords:  Cell viability; Doxorubicin; Microcell; NADPH; Paclitaxel; SK-MEL-28; cancer; cancer resistance
    DOI:  https://doi.org/10.1186/s12885-021-08813-5
  8. Mol Cell Oncol. 2021 ;8(4): 1976582
    The SWI/SNF complex, transcription-replication conflicts and cancer: a connection with high therapeutic potential.
    Aleix Bayona-Feliu, Andrés Aguilera.
      Genome instability is a hallmark of cancer. ATP-dependent chromatin remodelers are frequently altered in cancer. We have recently reported that the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protects the genome by limiting R-loop-mediated genome instability, mainly that caused by transcription-replication conflicts. Here we discuss the significance and biomedical applications of this finding.
    Keywords:  Cancer; R-loops; SWI/SNF; cBAF; chromatin; epigenetics; genome instability; transcription-replication conflicts
    DOI:  https://doi.org/10.1080/23723556.2021.1976582
  9. Biomed Pharmacother. 2021 Oct 04. pii: S0753-3322(21)01036-2. [Epub ahead of print]144 112252
    Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms.
    Yingqing Chen, Xiaomin Shao, Xiangge Zhao, Yuan Ji, Xiaorong Liu, Peixuan Li, Mingyu Zhang, Qianqian Wang.
      The protein arginine methyltransferase 5 (PRMT5) as the major type II arginine methyltransferase catalyzes the mono- and symmetric dimethylation of arginine residues in both histone and non-histone proteins. Recently, increasing evidence has demonstrated that PRMT5 plays an indispensable role in the occurrence and development of various human cancers by promoting the cell proliferation, invasion, and migration. It has become a promising and valuable target in the cancer epigenetic therapy. This review is to summarize the clinical significance of PRMT5 in the cancers such as lung cancer, breast cancer and colorectal cancer, and the drug discovery targeting PRMT5. Importantly, the existing PRMT5 inhibitors representing different molecular mechanisms, and their pharmacological effect, mechanism of action and biological affinity are analyzed. Clinical status, current problems and future perspective of PRMT5 inhibitors for the treatment of cancers are also discussed, all of which provides crucial help for the future discovery of PRMT5 targeted drugs for cancer treatment.
    Keywords:  Cancer; Histone methylation; Inhibitors; PRMT5
    DOI:  https://doi.org/10.1016/j.biopha.2021.112252
  10. Chembiochem. 2021 Oct 06.
    Chemical Biology Toolbox to Visualize Protein Aggregation in Live Cells.
    Di Shen, Yulong Bai, Yu Liu.
      Protein misfolding and aggregation is a complex biochemical process and has been associated with numerous human degenerative diseases. Developing novel tools and methods to visualize aggregated proteins in live cells is in high demand for mechanistic studies, diagnosis, and therapeutics. In this review, we summarized the recent progress on the chemical biology toolbox applied to protein aggregation studies in live cells. These methods exploited fluorescent protein tags, chemical protein tags, and small molecule probes to visualize protein aggregation process, detect proteome stresses, and quantify protein homeostasis network capacity. Inspired by these seminal works, we generalized design principles to develop new detection methods and probes that illuminate this important biological process in the future.
    Keywords:  protein aggregation, fluorescent protein, AggTag, proteostasis capacity sensor, small molecule probe
    DOI:  https://doi.org/10.1002/cbic.202100443
  11. Hum Cell. 2021 Oct 09.
    TRIM59 promotes osteosarcoma progression via activation of STAT3.
    Guoxing Xu, Zhenjiang Ma, Fei Yang, Yanqiang Bai, Jian Li, Wanglin Luo, Jiangbo Zhong.
      Osteosarcoma (OS) is a common, highly malignant bone tumor. Tripartite motif-containing protein 59 (TRIM59) has been identified as a potential oncogenic protein involved in the initiation and progression of various human carcinomas. Nonetheless, the possible roles and molecular mechanisms of action of TRIM59 in OS remain unclear. In this study, we found that TRIM59 expression levels were frequently upregulated in OS tissues and cell lines. TRIM59 knockdown significantly suppressed the proliferation, migration, and invasion of OS cells and promoted OS cell apoptosis, whereas TRIM59 overexpression had the opposite effects. In vivo experiments demonstrated that TRIM59 knockdown suppressed OS tumor growth and metastasis in vivo. Furthermore, we found that TRIM59 directly interacted with phospho-STAT3 in OS cells. The downregulation of STAT3 levels attenuated TRIM59-induced cell proliferation and invasion. Taken together, our results indicate that TRIM59 promoted OS progression via STAT3 activation. Therefore, our study may provide a novel therapeutic target for OS.
    Keywords:  Cell proliferation; Osteosarcoma; STAT3; TRIM59; Tumor invasion
    DOI:  https://doi.org/10.1007/s13577-021-00615-y
  12. NAR Cancer. 2021 Dec;3(4): zcab039
    Polycomb group proteins in cancer: multifaceted functions and strategies for modulation.
    Sijie Wang, Sandra C Ordonez-Rubiano, Alisha Dhiman, Guanming Jiao, Brayden P Strohmier, Casey J Krusemark, Emily C Dykhuizen.
      Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.
    DOI:  https://doi.org/10.1093/narcan/zcab039
  13. Nat Rev Cancer. 2021 Oct 05.
    Evolving cancer-niche interactions and therapeutic targets during bone metastasis.
    Robert L Satcher, Xiang H-F Zhang.
      Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.
    DOI:  https://doi.org/10.1038/s41568-021-00406-5
  14. PLoS Comput Biol. 2021 Oct 05. 17(10): e1009465
    DeepCellState: An autoencoder-based framework for predicting cell type specific transcriptional states induced by drug treatment.
    Ramzan Umarov, Yu Li, Erik Arner.
      Drug treatment induces cell type specific transcriptional programs, and as the number of combinations of drugs and cell types grows, the cost for exhaustive screens measuring the transcriptional drug response becomes intractable. We developed DeepCellState, a deep learning autoencoder-based framework, for predicting the induced transcriptional state in a cell type after drug treatment, based on the drug response in another cell type. Training the method on a large collection of transcriptional drug perturbation profiles, prediction accuracy improves significantly over baseline and alternative deep learning approaches when applying the method to two cell types, with improved accuracy when generalizing the framework to additional cell types. Treatments with drugs or whole drug families not seen during training are predicted with similar accuracy, and the same framework can be used for predicting the results from other interventions, such as gene knock-downs. Finally, analysis of the trained model shows that the internal representation is able to learn regulatory relationships between genes in a fully data-driven manner.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009465
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