bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021‒09‒12
twenty-one papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse.
  2. Visualization of chromatin higher-order structures and dynamics in live cells.
  3. DNA methylation and histone variants in aging and cancer.
  4. A common signature of cellular senescence; does it exist?
  5. Microtubule associated proteins as targets for anticancer drug development.
  6. Learning interpretable cellular and gene signature embeddings from single-cell transcriptomic data.
  7. CancerMIRNome: an interactive analysis and visualization database for miRNome profiles of human cancer.
  8. Drug resistance in colorectal cancer: An epigenetic overview.
  9. Predicting drug sensitivity of cancer cells based on DNA methylation levels.
  10. Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells.
  11. Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.
  12. VeloViz: RNA velocity informed embeddings for visualizing cellular trajectories.
  13. Beyond Single-Cell Analysis of Metallodrugs by ICP-MS: Targeting Cellular Substructures.
  14. Autophagic flux in cancer cells at the invasive front in the tumor-stroma border.
  15. The contributory roles of histone deacetylases (HDACs) in hematopoiesis regulation and possibilities for pharmacologic interventions in hematologic malignancies.
  16. Effect of the Notch1-mediated PI3K-Akt-mTOR pathway in human osteosarcoma.
  17. Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma.
  18. Cancer-Nano-Interaction: From Cellular Uptake to Mechanobiological Responses.
  19. The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.
  20. Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives.
  21. They Might Cut It-Lysosomes and Autophagy in Mitotic Progression.
  1. Nat Commun. 2021 Sep 06. 12(1): 5307
    Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse.
    S Taavitsainen, N Engedal, S Cao, F Handle, A Erickson, S Prekovic, D Wetterskog, T Tolonen, E M Vuorinen, A Kiviaho, R Nätkin, T Häkkinen, W Devlies, S Henttinen, R Kaarijärvi, M Lahnalampi, H Kaljunen, K Nowakowska, H Syvälä, M Bläuer, P Cremaschi, F Claessens, T Visakorpi, T L J Tammela, T Murtola, K J Granberg, A D Lamb, K Ketola, I G Mills, G Attard, W Wang, M Nykter, A Urbanucci.
      Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.
    DOI:  https://doi.org/10.1038/s41467-021-25624-1
  2. BMB Rep. 2021 Sep 07. pii: 5415. [Epub ahead of print]
    Visualization of chromatin higher-order structures and dynamics in live cells.
    Tae Lim Park, YigJi Lee, Won-Ki Cho.
      Chromatin has highly organized structures in the nucleus, and these higher-order structures are proposed to regulate gene activities and cellular processes. Sequencing-based techniques, such as Hi-C, and fluorescent in situ hybridization (FISH) have revealed a spatial segregation of active and inactive compartments of chromatin, as well as the non-random positioning of chromosomes in the nucleus, respectively. However, regardless of their efficiency in capturing target genomic sites, these techniques are limited to fixed cells. Since chromatin has dynamic structures, live cell imaging techniques are highlighted for their ability to detect conformational changes in chromatin at a specific time point, or to track various arrangements of chromatin through long-term imaging. Given that the imaging approaches to study live cells are dramatically advanced, we recapitulate methods that are widely used to visualize the dynamics of higher-order chromatin structures.
  3. Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00076-9. [Epub ahead of print]364 1-110
    DNA methylation and histone variants in aging and cancer.
    Adèle Mangelinck, Carl Mann.
      Aging-related diseases such as cancer can be traced to the accumulation of molecular disorder including increased DNA mutations and epigenetic drift. We provide a comprehensive review of recent results in mice and humans on modifications of DNA methylation and histone variants during aging and in cancer. Accumulated errors in DNA methylation maintenance lead to global decreases in DNA methylation with relaxed repression of repeated DNA and focal hypermethylation blocking the expression of tumor suppressor genes. Epigenetic clocks based on quantifying levels of DNA methylation at specific genomic sites is proving to be a valuable metric for estimating the biological age of individuals. Histone variants have specialized functions in transcriptional regulation and genome stability. Their concentration tends to increase in aged post-mitotic chromatin, but their effects in cancer are mainly determined by their specialized functions. Our increased understanding of epigenetic regulation and their modifications during aging has motivated interventions to delay or reverse epigenetic modifications using the epigenetic clocks as a rapid readout for efficacity. Similarly, the knowledge of epigenetic modifications in cancer is suggesting new approaches to target these modifications for cancer therapy.
    Keywords:  Aging; Cancer; DNA methylation; Epigenetic clocks; Epigenetics; Histone variants; Senescence
    DOI:  https://doi.org/10.1016/bs.ircmb.2021.06.002
  4. Ageing Res Rev. 2021 Sep 06. pii: S1568-1637(21)00205-1. [Epub ahead of print] 101458
    A common signature of cellular senescence; does it exist?
    Ewa Sikora, Anna Bielak-Zmijewska, Grazyna Mosieniak.
      Cellular senescence is a stress response, which can be evoked in all type of somatic cells by different stimuli. Senescent cells accumulate in the body and participate in aging and aging-related diseases mainly by their secretory activity, commonly known as senescence-associated secretory phenotype-SASP. Senescence is typically described as cell cycle arrest. This definition stems from the original observation concerning limited cell division potential of human fibroblasts in vitro. At present, the process of cell senescence is attributed also to cancer cells and to non-proliferating post-mitotic cells. Many cellular signaling pathways and specific and unspecific markers contribute to the complex, dynamic and heterogeneous phenotype of senescent cells. Considering the diversity of cells that can undergo senescence upon different inducers and variety of mechanisms involved in the execution of this process, we ask if there is a common signature of cell senescence. It seems that cell cycle arrest in G0, G1 or G2 is indispensable for cell senescence; however, to ensure irreversibility of divisions, the exit from the cell cycle to the state, which we call a GS (Gero Stage), is necessary. The DNA damage, changes in nuclear architecture and chromatin rearrangement are involved in signaling pathways leading to altered gene transcription and secretion of SASP components. Thus, nuclear changes and SASP are vital features of cell senescence that, together with temporal arrest in the cell cycle (G1 or/and G2), which may be followed by polyploidisation/depolyploidisation or exit from the cell cycle leading to permanent proliferation arrest (GS), define the signature of cellular senescence.
    Keywords:  aging; atypical cell divisions; autophagy; cell cycle; cellular senescence; chromatin reorganization; nuclear structure, polyploidisation; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.arr.2021.101458
  5. Bioorg Chem. 2021 Sep 01. pii: S0045-2068(21)00697-0. [Epub ahead of print]116 105320
    Microtubule associated proteins as targets for anticancer drug development.
    Sadiya Khwaja, Kapil Kumar, Ranjana Das, Arvind Singh Negi.
      The dynamic equilibrium of tubulin-microtubule is an essential aspect of cell survivality. Modulation of this dynamics has become an important target for the cancer drug development. Tubulin exists in the alpha-beta dimer form which polymerizes to form microtubule and further depolymerizes back to tubulin dimer. The microtubule plays an essential role in mitosis and cell multiplication. Antitubulin drugs disturb the microtubule dynamics which is essentially required for DNA segregation and cell division during mitosis so killing the cancerous cells. Microtubule Associated Proteins (MAPs) interact with cellular cytoskeletal microtubules. MAPs bind to the either polymerized or depolymerized tubulin dimers within the cell and mostly causing stabilization of microtubules. Some of the tubulin binding drugs are in clinical use and others in clinical trial. MAPs inhibitors are also in clinical trial. Post-translational modification of lysine-40 either in histone or in alpha tubulin has an important role in gene expression and is balanced between histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDAC inhibitors have the anticancer properties to form a drug for the treatment of cancer. They act by inducing cell cycle arrest and cell death. Some of the HDAC inhibitors are approved to be used as anticancer drug while others are under different phases of clinical trial. The present review updates on various MAPs, their role in cancer progression, MAPs inhibitors and their future prospects.
    Keywords:  Cancer chemotherapeutics; Histone acetyl transferase; Histone deacetylase; Microtubule associated proteins; Tubulin
    DOI:  https://doi.org/10.1016/j.bioorg.2021.105320
  6. Nat Commun. 2021 09 06. 12(1): 5261
    Learning interpretable cellular and gene signature embeddings from single-cell transcriptomic data.
    Yifan Zhao, Huiyu Cai, Zuobai Zhang, Jian Tang, Yue Li.
      The advent of single-cell RNA sequencing (scRNA-seq) technologies has revolutionized transcriptomic studies. However, large-scale integrative analysis of scRNA-seq data remains a challenge largely due to unwanted batch effects and the limited transferabilty, interpretability, and scalability of the existing computational methods. We present single-cell Embedded Topic Model (scETM). Our key contribution is the utilization of a transferable neural-network-based encoder while having an interpretable linear decoder via a matrix tri-factorization. In particular, scETM simultaneously learns an encoder network to infer cell type mixture and a set of highly interpretable gene embeddings, topic embeddings, and batch-effect linear intercepts from multiple scRNA-seq datasets. scETM is scalable to over 106 cells and confers remarkable cross-tissue and cross-species zero-shot transfer-learning performance. Using gene set enrichment analysis, we find that scETM-learned topics are enriched in biologically meaningful and disease-related pathways. Lastly, scETM enables the incorporation of known gene sets into the gene embeddings, thereby directly learning the associations between pathways and topics via the topic embeddings.
    DOI:  https://doi.org/10.1038/s41467-021-25534-2
  7. Nucleic Acids Res. 2021 Sep 09. pii: gkab784. [Epub ahead of print]
    CancerMIRNome: an interactive analysis and visualization database for miRNome profiles of human cancer.
    Ruidong Li, Han Qu, Shibo Wang, John M Chater, Xuesong Wang, Yanru Cui, Lei Yu, Rui Zhou, Qiong Jia, Ryan Traband, Meiyue Wang, Weibo Xie, Dongbo Yuan, Jianguo Zhu, Wei-De Zhong, Zhenyu Jia.
      MicroRNAs (miRNAs), which play critical roles in gene regulatory networks, have emerged as promising diagnostic and prognostic biomarkers for human cancer. In particular, circulating miRNAs that are secreted into circulation exist in remarkably stable forms, and have enormous potential to be leveraged as non-invasive biomarkers for early cancer detection. Novel and user-friendly tools are desperately needed to facilitate data mining of the vast amount of miRNA expression data from The Cancer Genome Atlas (TCGA) and large-scale circulating miRNA profiling studies. To fill this void, we developed CancerMIRNome, a comprehensive database for the interactive analysis and visualization of miRNA expression profiles based on 10 554 samples from 33 TCGA projects and 28 633 samples from 40 public circulating miRNome datasets. A series of cutting-edge bioinformatics tools and machine learning algorithms have been packaged in CancerMIRNome, allowing for the pan-cancer analysis of a miRNA of interest across multiple cancer types and the comprehensive analysis of miRNome profiles to identify dysregulated miRNAs and develop diagnostic or prognostic signatures. The data analysis and visualization modules will greatly facilitate the exploit of the valuable resources and promote translational application of miRNA biomarkers in cancer. The CancerMIRNome database is publicly available at http://bioinfo.jialab-ucr.org/CancerMIRNome.
    DOI:  https://doi.org/10.1093/nar/gkab784
  8. Biochim Biophys Acta Rev Cancer. 2021 Sep 01. pii: S0304-419X(21)00121-9. [Epub ahead of print]1876(2): 188623
    Drug resistance in colorectal cancer: An epigenetic overview.
    Maochao Luo, Xingyue Yang, Hai-Ning Chen, Edouard C Nice, Canhua Huang.
      Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Despite significant progress that has been made in therapies against CRC over the past decades, drug resistance is still a major limitation in CRC treatment. Numerous investigations have unequivocally shown that epigenetic regulation plays an important role in CRC drug resistance because of the high rate of epigenetic alterations in multiple genes during cancer development or drug treatment. Furthermore, the reversibility of epigenetic alterations provides novel therapeutic strategies to overcome drug resistance using small molecules, which can target non-coding RNAs or reverse histone modification and DNA methylation. In this review, we discuss epigenetic regulation in CRC drug resistance and the possible role of preventing or reversing CRC drug resistance using epigenetic therapy in CRC treatment.
    Keywords:  Colorectal cancer; DNA methylation; Drug resistance; Histone modification; Noncoding RNA
    DOI:  https://doi.org/10.1016/j.bbcan.2021.188623
  9. PLoS One. 2021 ;16(9): e0238757
    Predicting drug sensitivity of cancer cells based on DNA methylation levels.
    Sofia P Miranda, Fernanda A Baião, Julia L Fleck, Stephen R Piccolo.
      Cancer cell lines, which are cell cultures derived from tumor samples, represent one of the least expensive and most studied preclinical models for drug development. Accurately predicting drug responses for a given cell line based on molecular features may help to optimize drug-development pipelines and explain mechanisms behind treatment responses. In this study, we focus on DNA methylation profiles as one type of molecular feature that is known to drive tumorigenesis and modulate treatment responses. Using genome-wide, DNA methylation profiles from 987 cell lines in the Genomics of Drug Sensitivity in Cancer database, we used machine-learning algorithms to evaluate the potential to predict cytotoxic responses for eight anti-cancer drugs. We compared the performance of five classification algorithms and four regression algorithms representing diverse methodologies, including tree-, probability-, kernel-, ensemble-, and distance-based approaches. We artificially subsampled the data to varying degrees, aiming to understand whether training based on relatively extreme outcomes would yield improved performance. When using classification or regression algorithms to predict discrete or continuous responses, respectively, we consistently observed excellent predictive performance when the training and test sets consisted of cell-line data. Classification algorithms performed best when we trained the models using cell lines with relatively extreme drug-response values, attaining area-under-the-receiver-operating-characteristic-curve values as high as 0.97. The regression algorithms performed best when we trained the models using the full range of drug-response values, although this depended on the performance metrics we used. Finally, we used patient data from The Cancer Genome Atlas to evaluate the feasibility of classifying clinical responses for human tumors based on models derived from cell lines. Generally, the algorithms were unable to identify patterns that predicted patient responses reliably; however, predictions by the Random Forests algorithm were significantly correlated with Temozolomide responses for low-grade gliomas.
    DOI:  https://doi.org/10.1371/journal.pone.0238757
  10. Anticancer Agents Med Chem. 2021 Aug 31.
    Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells.
    Gopikrishna Moku, Swathi Vangala, Venu Yakati, Chaitanya Chakravarthi Gali, Soumen Saha, Vijay Sagar Madamsetty, Amber Vyas.
      BACKGROUND: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers.AIM: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents.
    METHODS: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays.
    RESULTS: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 µM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 µM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs.
    CONCLUSION: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.
    Keywords:  Angiogenesis; HDAC inhibitors; SAHA analogs; anti-cancer activity; apoptosis; cell cycle arrest
    DOI:  https://doi.org/10.2174/1871520621666210901102425
  11. Biochim Biophys Acta Mol Basis Dis. 2021 Sep 03. pii: S0925-4439(21)00198-8. [Epub ahead of print] 166265
    Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.
    Yongqiang Chen, Spencer B Gibson.
      Autophagy is an intracellular lysosomal degradation process involved in multiple facets of cancer biology. Various dimensions of autophagy are associated with tumor growth and cancer progression, and here we focus on the dimensions involved in regulation of cell survival/cell death, cell proliferation and tumor dormancy. The first dimension of autophagy supports cell survival under stress within tumors and under certain contexts drives cell death, impacting tumor growth. The second dimension of autophagy promotes proliferation through directly regulating cell cycle or indirectly maintaining metabolism, increasing tumor growth. The third dimension of autophagy facilitates tumor cell dormancy, contributing to cancer treatment resistance and cancer recurrence. The intricate relationship between these three dimensions of autophagy influences the extent of tumor growth and cancer progression. In this review, we summarize the roles of the three dimensions of autophagy in tumor growth and cancer progression, and discuss unanswered questions in these fields.
    Keywords:  Autophagy; Cell death; Cell survival; Proliferation; Tumor dormacy; Tumor growth
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166265
  12. Bioinformatics. 2021 Sep 09. pii: btab653. [Epub ahead of print]
    VeloViz: RNA velocity informed embeddings for visualizing cellular trajectories.
    Lyla Atta, Arpan Sahoo, Jean Fan.
      MOTIVATION: Single cell transcriptomics profiling technologies enable genome-wide gene expression measurements in individual cells but can currently only provide a static snapshot of cellular transcriptional states. RNA velocity analysis can help infer cell state changes using such single cell transcriptomics data. To interpret these cell state changes inferred from RNA velocity as part of underlying cellular trajectories, current approaches rely on visualization with principal components, t-distributed stochastic neighbor embedding, and other 2D embeddings derived from the observed single cell transcriptional states. However, these 2D embeddings can yield different representations of the underlying cellular trajectories, hindering the interpretation of cell state changes.RESULTS: We developed VeloViz to create RNA-velocity-informed 2D and 3D embeddings from single cell transcriptomics data. Using both real and simulated data, we demonstrate that VeloViz embeddings are able to capture underlying cellular trajectories across diverse trajectory topologies, even when intermediate cell states may be missing. By taking into consideration the predicted future transcriptional states from RNA velocity analysis, VeloViz can help visualize a more reliable representation of underlying cellular trajectories.
    AVAILABILITY: Source code is available on GitHub (http://github.com/JEFworks-Lab/veloviz) and Bioconductor (http://bioconductor.org/packages/veloviz) with additional tutorials at https://JEF.works/veloviz/.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btab653
  13. Int J Mol Sci. 2021 Aug 31. pii: 9468. [Epub ahead of print]22(17):
    Beyond Single-Cell Analysis of Metallodrugs by ICP-MS: Targeting Cellular Substructures.
    Audrey Galé, Lukas Hofmann, Nicola Lüdi, Martin Nils Hungerbühler, Christoph Kempf, Johannes Thomas Heverhagen, Hendrik von Tengg-Kobligk, Peter Broekmann, Nico Ruprecht.
      Platinum compounds such as cisplatin (cisPt) embody the backbone of combination chemotherapy protocols against advanced lung cancer. However, their efficacy is primarily limited by inherent or acquired platinum resistance, the origin of which has not been fully elucidated yet, although of paramount interest. Using single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), this study quantifies cisPt in single cancer cells and for the first time in isolated nuclei. A comparison of cisPt uptake was performed between a wild type (wt) cancer cell line and related resistant sublines. In both, resistant cells, wt cells, and their nuclei, cisPt uptake was measured at different incubation times. A lower amount of cisPt was found in resistant cell lines and their nuclei compared to wt cells. Moreover, the abundance of internalized cisPt decreased with increasing resistance. Interestingly, concentrations of cisPt found within the nuclei were higher than compared to cellular concentrations. Here, we show, that SC-ICP-MS allows precise and accurate quantification of metallodrugs in both single cells and cell organelles such as nuclei. These findings pave the way for future applications investigating the potency and efficacy of novel metallodrugs developed for cancer treatment.
    Keywords:  NSCLC; chemotherapy; cisplatin; cisplatin resistance; nuclear uptake; single cell ICP-MS
    DOI:  https://doi.org/10.3390/ijms22179468
  14. Aging (Albany NY). 2021 Aug 17. 13(16): 20229-20245
    Autophagic flux in cancer cells at the invasive front in the tumor-stroma border.
    Fei Yan, Xuexi Zhang, Rongying Tan, Mingchen Li, Zengtuan Xiao, Hao Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu.
      Cancer cells at the invasive front directly interact with stromal tissue that provides a microenvironment with mechanical, nutrient, and oxygen supply characteristics distinct from those of intratumoral tissues. It has long been known that cancer cells at the invasive front and cancer cells inside the tumor body exhibit highly differentiated functions and behaviors. However, it is unknown whether cancer cells at different locations exhibit a variety of autophagic flux, an important catabolic process to maintain cellular homeostasis in response to environmental changes. Here, using transmission electron microscopy (TEM), we found that invading cancer cells at the invasive front, which show mesenchymal transcriptomic traits, exhibit higher autophagic flux than cancer cells inside the tumor body in human primary non-small cell lung cancer (NSCLC) tissues. This autophagic feature was further confirmed by a live cell autophagic flux monitoring system combined with a 3D organotypic invasion coculture system. Additionally, the increased autophagic flux endows cancer cells with invasive behavior and positively correlates with the advanced tumor stages and the reduced survival period of lung cancer patients. These findings expand the understanding of autophagic dynamics during cancer invasion.
    Keywords:  autophagy; invasion; invasive front; lung cancer; tumor-stroma border
    DOI:  https://doi.org/10.18632/aging.203406
  15. Int Immunopharmacol. 2021 Sep 03. pii: S1567-5769(21)00750-5. [Epub ahead of print]100 108114
    The contributory roles of histone deacetylases (HDACs) in hematopoiesis regulation and possibilities for pharmacologic interventions in hematologic malignancies.
    Mahdieh Mehrpouri, Atieh Pourbagheri-Sigaroodi, Davood Bashash.
      Although the definitive role of epigenetic modulations in a wide range of hematologic malignancies, spanning from leukemia to lymphoma and multiple myeloma, has been evidenced, few articles reviewed the task. Given the high accessibility of histone deacetylase (HDACs) to necessary transcription factors involved in hematopoiesis, this review aims to outline physiologic impacts of these enzymes in normal hematopoiesis, and also to outline the original data obtained from international research laboratories on their regulatory role in the differentiation and maturation of different hematopoietic lineages. Questions on how aberrant expression of HDACs contributes to the formation of hematologic malignancies are also responded, because these classes of enzymes have a respectable share in the development, progression, and recurrence of leukemia, lymphoma, and multiple myeloma. The last section provides a special focus on the therapeutic perspectiveof HDACs inhibitors, either as single agents or in a combined-modal strategy, in these neoplasms. In conclusion, optimizing the dose and the design of more patient-tailored inhibitors, while maintaining low toxicity against normal cells, will help improve clinical outcomes of HDAC inhibitors in hematologic malignancies.
    Keywords:  Epigenetics; HDAC; HDAC inhibitors; Hematologic malignancies; Hematopoiesis; Histone deacetylase
    DOI:  https://doi.org/10.1016/j.intimp.2021.108114
  16. Aging (Albany NY). 2021 Sep 08. 13(undefined):
    Effect of the Notch1-mediated PI3K-Akt-mTOR pathway in human osteosarcoma.
    Kexiang Zhang, Song Wu, Hongwei Wu, Li Liu, Jiahui Zhou.
      PURPOSE: Osteosarcoma is one of the most common malignant bone tumours in early adolescence. The incidence rate of osteosarcoma has stagnated over the past 30 years, highlighting the need to develop novel therapies. In osteosarcoma cells, Notch1 expression is absent, and the Notch1 pathway is related to cancer cell proliferation, apoptosis and autophagy. Our study aimed to investigate the role of Notch1 in osteosarcoma development.METHODS: We measured NICD1 expression induced by doxycycline treatment at various concentrations. The viability of human osteosarcoma cells (MG-63) induced by doxycycline was measured. Flow cytometry and cell apoptosis analysis were conducted to measure the effect of Notch1 on the cell cycle of human osteosarcoma cells. We also used a GFP-LC3 plasmid to detect Notch1-induced autophagy in MG-63 cells. Western blotting was conducted to analyse expression of the PI3K/Akt/mTOR signalling pathway through Notch1 induction by doxycycline.
    RESULTS: In this study, we demonstrated that Notch1 activation by doxycycline potently suppressed cell proliferation by inducing S phase arrest in osteosarcoma cells. Doxycycline-induced Notch1 activation also induced apoptosis and autophagy in osteosarcoma cells. Moreover, we found that Notch1 inhibited PI3K/Akt/mTOR signalling to induce apoptosis and autophagy.
    CONCLUSION: In summary, our results revealed that Notch1 activation by doxycycline induces S phase arrest, apoptosis and autophagy by blocking PI3K/Akt/mTOR signalling in human osteosarcoma cells. Notch1 may be a potential clinical antitumour target for osteosarcoma therapy.
    Keywords:  Notch1; PI3K/Akt/mTOR; autophagy; osteosarcoma
    DOI:  https://doi.org/10.18632/aging.203261
  17. Cancers (Basel). 2021 Sep 05. pii: 4476. [Epub ahead of print]13(17):
    Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma.
    Michael Müller, Lisa Rösch, Sara Najafi, Charlotte Gatzweiler, Johannes Ridinger, Xenia F Gerloff, David T W Jones, Jochen Baßler, Sina Kreth, Sabine Stainczyk, Karen Frese, Benjamin Meder, Frank Westermann, Till Milde, Heike Peterziel, Olaf Witt, Ina Oehme.
      APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.
    Keywords:  ROS; TP53; histone deacetylases; pediatric tumors of the nervous system; precision medicine; response prediction biomarker; small molecule inhibitors
    DOI:  https://doi.org/10.3390/cancers13174476
  18. Int J Mol Sci. 2021 Sep 03. pii: 9587. [Epub ahead of print]22(17):
    Cancer-Nano-Interaction: From Cellular Uptake to Mechanobiological Responses.
    Ahmad Sohrabi Kashani, Muthukumaran Packirisamy.
      With the advancement of nanotechnology, the nano-bio-interaction field has emerged. It is essential to enhance our understanding of nano-bio-interaction in different aspects to design nanomedicines and improve their efficacy for therapeutic and diagnostic applications. Many researchers have extensively studied the toxicological responses of cancer cells to nano-bio-interaction, while their mechanobiological responses have been less investigated. The mechanobiological properties of cells such as elasticity and adhesion play vital roles in cellular functions and cancer progression. Many studies have noticed the impacts of cellular uptake on the structural organization of cells and, in return, the mechanobiology of human cells. Mechanobiological changes induced by the interactions of nanomaterials and cells could alter cellular functions and influence cancer progression. Hence, in addition to biological responses, the possible mechanobiological responses of treated cells should be monitored as a standard methodology to evaluate the efficiency of nanomedicines. Studying the cancer-nano-interaction in the context of cell mechanics takes our knowledge one step closer to designing safe and intelligent nanomedicines. In this review, we briefly discuss how the characteristic properties of nanoparticles influence cellular uptake. Then, we provide insight into the mechanobiological responses that may occur during the nano-bio-interactions, and finally, the important measurement techniques for the mechanobiological characterizations of cells are summarized and compared. Understanding the unknown mechanobiological responses to nano-bio-interaction will help with developing the application of nanoparticles to modulate cell mechanics for controlling cancer progression.
    Keywords:  cancer cells; cell mechanics; mechanobiological properties; migratory index; nano-bio-interaction; nanoparticle
    DOI:  https://doi.org/10.3390/ijms22179587
  19. Autophagy. 2021 Sep 05. 1-3
    The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.
    Yumiko Oshima, Nicolas Verhoeven, Etienne Cartier, Mariusz Karbowski.
      Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Formation of mosaic mitochondria requires mitochondrial fission and active mitochondrial translation. In cell lines deficient in PRKN activity, this process is followed by severing the outer mitochondrial membrane (OMM) and ubiquitination of the inner mitochondrial membrane (IMM) proteins (including TRAP1 and CPOX), recruitment of autophagy receptors, and formation of mito-autophagosomes. In contrast, in PRKN-expressing cells, mitochondria with high CYCS and CPOX levels are preferentially targeted by PRKN, leading to OMM ubiquitination and canonical PRKN-PINK1-mediated autophagy.
    Keywords:  DRP1; Parkin; mitochondria; mitochondrial translation; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2021.1964887
  20. J Med Chem. 2021 Sep 07.
    Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives.
    Aarajana Shrestha, Nayeon Kim, Su-Jeong Lee, Yong Hyun Jeon, Ji-Joon Song, Hongchan An, Sung Jin Cho, Tara Man Kadayat, Jungwook Chin.
      Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c01116
  21. Front Cell Dev Biol. 2021 ;9 727538
    They Might Cut It-Lysosomes and Autophagy in Mitotic Progression.
    Saara Hämälistö, Jonathan Stahl-Meyer, Marja Jäättelä.
      The division of one cell into two looks so easy, as if it happens without any control at all. Mitosis, the hallmark of mammalian life is, however, tightly regulated from the early onset to the very last phase. Despite the tight control, errors in mitotic division occur frequently and they may result in various chromosomal instabilities and malignancies. The flow of events during mitotic progression where the chromosomes condensate and rearrange with the help of the cytoskeletal network has been described in great detail. Plasma membrane dynamics and endocytic vesicle movement upon deadhesion and reattachment of dividing cells are also demonstrated to be functionally important for the mitotic integrity. Other cytoplasmic organelles, such as autophagosomes and lysosomes, have until recently been considered merely as passive bystanders in this process. Accordingly, at the onset of nuclear envelope breakdown in prometaphase, the number of autophagic structures and lysosomes is reduced and the bulk autophagic machinery is suppressed for the duration of mitosis. This is believed to ensure that the exposed nuclear components are not unintentionally delivered to autophagic degradation. With the evolving technologies that allow the detection of subtle alterations in cytoplasmic organelles, our understanding of the small-scale regulation of intracellular organelles has deepened rapidly and we discuss here recent discoveries revealing unexpected roles for autophagy and lysosomes in the preservation of genomic integrity during mitosis.
    Keywords:  autophagy; cathepsin B; chromosome segregation; lysosome; mitosis; spindle
    DOI:  https://doi.org/10.3389/fcell.2021.727538
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