bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021–09–19
24 papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells.
  2. P53-regulated autophagy and its impact on drug resistance and cell fate.
  3. Circulating Tumor Cells (CTCs): A Unique Model of Cancer Metastases and Non-invasive Biomarkers of Therapeutic Response.
  4. Emerging Roles of LncRNAs in the EZH2-regulated Oncogenic Network.
  5. Classical HDACs in the regulation of neuroinflammation.
  6. The roles of epigenetics in cancer progression and metastasis.
  7. Histone Deacetylases and their Inhibitors in Colorectal Cancer Therapy: Current Evidence and Future Considerations.
  8. Chromatin accessibility regulates chemotherapy-induced dormancy and reactivation.
  9. Long Non-Coding RNAs as Potential Diagnostic and Prognostic Biomarkers in Breast Cancer: Progress and Prospects.
  10. Recent advances in the contribution of circRNAs to cisplatin chemotherapy resistance in cancers.
  11. FACT-seq: profiling histone modifications in formalin-fixed paraffin-embedded samples with low cell numbers.
  12. The evolution of evolutionary processes in organismal and cancer evolution.
  13. Single nucleus RNA-sequencing: how it's done, applications and limitations.
  14. Modeling glioblastoma heterogeneity as a dynamic network of cell states.
  15. Single-cell analyses reveal mechanisms of cancer stem cell maintenance and epithelial-mesenchymal transition in recurrent bladder cancer.
  16. Investigating Lysosomal Autophagy via Surface-Enhanced Raman Scattering Spectroscopy.
  17. Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro.
  18. How much can deep learning improve prediction of the responses to drugs in cancer cell lines?
  19. In silico methods and tools for drug discovery.
  20. MALAT-1 is Associated with the Doxorubicin Resistance in U-2OS Osteosarcoma Cells.
  21. Dynamic alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged-1 gene promoters cause an inflammatory switch of endothelial cells.
  22. Effects of YAP1 and SFRP2 overexpression on the biological behavior of colorectal cancer cells and their molecular mechanisms.
  23. Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.
  24. Autophagy-Related Genes and Long Noncoding RNAs Signatures as Predictive Biomarkers for Osteosarcoma Survival.
  1. Int J Biol Sci. 2021 ;17(13): 3381-3400
    Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells.
    Sijia Zhang, Lingjun Zhan, Xue Li, Zhenhong Yang, Yumin Luo, Haiping Zhao.
      Genetic changes are difficult to reverse; thus, epigenetic aberrations, including changes in DNA methylation, histone modifications, and noncoding RNAs, with potential reversibility, have attracted attention as pharmaceutical targets. The current paradigm is that histone deacetylases (HDACs) regulate gene expression via deacetylation of histone and nonhistone proteins or by forming corepressor complexes with transcription factors. The emergence of epigenetic tools related to HDACs can be used as diagnostic and therapeutic markers. HDAC inhibitors that block specific or a series of HDACs have proven to be a powerful therapeutic treatment for immune-related diseases. Here, we summarize the various roles of HDACs and HDAC inhibitors in the development and function of innate and adaptive immune cells and their implications for various diseases and therapies.
    Keywords:  Epigenetics; HDAC; astrocyte; dendritic cells; lymphocyte; macrophage; mast cells; microglia; neutrophils
    DOI:  https://doi.org/10.7150/ijbs.62001
  2. Cancer Drug Resist. 2021 ;4 85-95
    P53-regulated autophagy and its impact on drug resistance and cell fate.
    Daeun Shim, Lei Duan, Carl G Maki.
      Wild-type p53 is a stress-responsive transcription factor and a potent tumor suppressor. P53 inhibits the growth of incipient cancer cells by blocking their proliferation or inducing their death through apoptosis. Autophagy is a self-eating process that plays a key role in response to stress. During autophagy, organelles and other intracellular components are degraded in autophagolysosomes and the autophagic breakdown products are recycled into metabolic and energy producing pathways needed for survival. P53 can promote or inhibit autophagy depending on its subcellular localization, mutation status, and the level of stress. Blocking autophagy has been reported in several studies to increase p53-mediated apoptosis, revealing that autophagy can influence cell-fate in response to activated p53 and is a potential target to increase p53-dependent tumor suppression.
    Keywords:  Autophagy; histone methylation; metabolism
    DOI:  https://doi.org/10.20517/cdr.2020.85
  3. Front Genet. 2021 ;12 734595
    Circulating Tumor Cells (CTCs): A Unique Model of Cancer Metastases and Non-invasive Biomarkers of Therapeutic Response.
    Jialing Liu, Jingru Lian, Yafei Chen, Xin Zhao, ChangZheng Du, Yang Xu, Hailiang Hu, Hai Rao, Xin Hong.
      Late-stage cancer metastasis remains incurable in the clinic and is the major cause death in patients. Circulating tumor cells (CTCs) are thought to be metastatic precursors shed from the primary tumor or metastatic deposits and circulate in the blood. The molecular network regulating CTC survival, extravasation, and colonization in distant metastatic sites is poorly defined, largely due to challenges in isolating rare CTCs. Recent advances in CTC isolation and ex vivo culture techniques facilitates single-cell omics and the development of related animal models to study CTC-mediated metastatic progression. With these powerful tools, CTCs can potentially be used as non-invasive biomarkers predicting therapeutic response. These studies may open a new avenue for CTC-specific drug discoveries. In this short review, we aim to summarize recent progress in the characterization of CTCs and their clinical relevance in various cancers, setting the stage for realizing personalized therapies against metastases.
    Keywords:  cancer metastasis; circulating tumor cells; liquid biopsy; microfluidic engineering; non-invasive biomarker; therapeutic response
    DOI:  https://doi.org/10.3389/fgene.2021.734595
  4. Int J Biol Sci. 2021 ;17(13): 3268-3280
    Emerging Roles of LncRNAs in the EZH2-regulated Oncogenic Network.
    Aixin Hao, Yunxuan Wang, Daniel B Stovall, Yu Wang, Guangchao Sui.
      Cancer is a life-threatening disease, but cancer therapies based on epigenetic mechanisms have made great progress. Enhancer of zeste homolog 2 (EZH2) is the key catalytic component of Polycomb repressive complex 2 (PRC2) that mediates the tri-methylation of lysine 27 on histone 3 (H3K27me3), a well-recognized marker of transcriptional repression. Mounting evidence indicates that EZH2 is elevated in various cancers and associates with poor prognosis. In addition, many studies revealed that EZH2 is also involved in transcriptional repression dependent or independent of PRC2. Meanwhile, long non-coding RNAs (lncRNAs) have been reported to regulate numerous and diverse signaling pathways in oncogenesis. In this review, we firstly discuss functional interactions between EZH2 and lncRNAs that determine PRC2-dependent and -independent roles of EZH2. Secondly, we summarize the lncRNAs regulating EZH2 expression at transcription, post-transcription and post-translation levels. Thirdly, we review several oncogenic pathways cooperatively regulated by lncRNAs and EZH2, including the Wnt/β-catenin and p53 pathways. In conclusion, lncRNAs play a key role in the EZH2-regulated oncogenic network with many fertile directions to be explored.
    Keywords:  EZH2; H3K27me3; PRC2; cancer; epigenetic regulation; lncRNA; non-histone methylation
    DOI:  https://doi.org/10.7150/ijbs.63488
  5. Neurochem Int. 2021 Sep 09. pii: S0197-0186(21)00228-X. [Epub ahead of print] 105182
    Classical HDACs in the regulation of neuroinflammation.
    Yunjian Dai, Taofeng Wei, Zexu Shen, Yun Bei, Haoran Lin, Haibin Dai.
      Neuroinflammation is a key factor of the pathology of various neurological diseases (brain injury, depression, neurodegenerative diseases). It is a complex and orderly process that relies on various types of glial cells and peripheral immune cells. Inhibition of neuroinflammation can reduce the severity of neurological diseases. The initiation, progression, and termination of inflammation require gene activation, epigenetic modification, transcriptional translation, and post-translational regulation, all of which are tightly regulated by different enzymes. Epigenetics refers to the regulation of epigenetic gene expression by epigenetic changes (DNA methylation, histone modification, and non-coding RNAs such as miRNA) that are not dependent on changes in gene sequence and are heritable. Histone deacetylases (HDACs) are a group of important enzymes that regulate epigenetics. They can remove the acetyl group on the lysine ɛ-amino group of the target protein, thereby affecting gene transcription or altering protein activity. HDACs are involved in the regulation of immunity and inflammation. HDAC inhibitor (HDACi) has also become a new hotspot in the research of anti-inflammatory drugs. Therefore, the aim of the current review is to discuss and summarize the role and mechanism of different HDACs in neuroinflammation and the corresponding role of HDACi in neurological diseases, and to providing new ideas for future research on neuroinflammation-related diseases and drug development.
    Keywords:  Histone deacetylases; Histone deacetylases inhibitor; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuint.2021.105182
  6. Biochem J. 2021 Sep 17. 478(17): 3373-3393
    The roles of epigenetics in cancer progression and metastasis.
    Jocelyn F Chen, Qin Yan.
      Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. However, metastasis-specific genetic mutations have not been identified in most exome or genome sequencing studies. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. A variety of epigenetic mechanisms were identified to regulate metastasis, including the well-studied DNA methylation and histone modifications. In the past few years, large scale chromatin structure alterations including reprogramming of the enhancers and chromatin accessibility to the transcription factors were shown to be potential driving force of cancer metastasis. To dissect the molecular mechanisms and functional output of these epigenetic changes, it is critical to use advanced techniques and alternative animal models for interdisciplinary and translational research on this topic. Here we summarize our current understanding of epigenetic aberrations in cancer progression and metastasis, and their implications in developing new effective metastasis-specific therapies.
    Keywords:  cancer metastasis; chromatin opening; enhancer reprogramming; epigenetics; histone modification; tumor progression
    DOI:  https://doi.org/10.1042/BCJ20210084
  7. Curr Med Chem. 2021 Sep 14.
    Histone Deacetylases and their Inhibitors in Colorectal Cancer Therapy: Current Evidence and Future Considerations.
    Nikolaos Garmpis, Christos Damaskos, Anna Garmpi, Afroditi Nonni, Vasiliki E Georgakopoulou, Efstathios Antoniou, Dimitrios Schizas, Panagiotis Sarantis, Alexandros Patsouras, Athanasios Syllaios, Christos Vallilas, Evangelos Koustas, Konstantinos Kontzoglou, Nikolaos Trakas, Dimitrios Dimitroulis.
      Colorectal cancer (CRC) comprises a heterogeneous group of gastrointestinal tract tumors. It is a multifactorial disease, and a plethora of distinct factors are involved in its pathogenesis and pathophysiology. The development of CRC is not limited to genetic changes, but epigenetic and environmental factors are also involved. Among the epigenetic factors, histone deacetylases (HDACs), a group of epigenetic enzymes that regulate gene expression, have been reported to be over-expressed in CRC. HDACs and their inhibitors seem to play an important role in the molecular pathophysiology of CRC. The aim of this review was to define the role of HDAC inhibitors as potential anticancer agents against CRC.
    Keywords:  Colorectal Cancer; Deacetylase; Epigenetics; HDAC; HDACI; Histone; Inhibitors; Targeted Therapy
    DOI:  https://doi.org/10.2174/0929867328666210915105929
  8. Mol Ther Nucleic Acids. 2021 Dec 03. 26 269-279
    Chromatin accessibility regulates chemotherapy-induced dormancy and reactivation.
    Lujuan Wang, Qiu Peng, Na Yin, Yaohuan Xie, Jiaqi Xu, Anqi Chen, Junqi Yi, Jingqun Tang, Juanjuan Xiang.
      Cisplatin-based chemotherapy remains the standard care for non-small cell lung cancer (NSCLC) patients. Relapse after chemotherapy-induced dormancy affects the overall survival of patients. The evolution of cancer cells under chemotherapy stress is regulated by transcription factors (TFs) with binding sites initially buried deep within inaccessible chromatin. The transcription machinery and dynamic epigenetic alterations during the process of dormancy-reactivation of lung cancer cells after chemotherapy need to be investigated. Here, we investigated the chromatin accessibility of lung cancer cells after cisplatin treatment, using an assay for transposase-accessible chromatin sequencing (ATAC-seq). We observed that global chromatin accessibility was extensively improved. Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) v.2 was used to elucidate TF-target interaction during the process of dormancy and reactivation. Enhancer regions and motifs specific to key TFs including JUN, MYC, SMAD3, E2F1, SP1, CTCF, SMAD4, STAT3, NFKB1, and KLF4 were enriched in differential loci ATAC-seq peaks of dormant and reactivated cancer cells induced by chemotherapy. The findings suggest that these key TFs regulated gene expressions during the process of dormancy and reactivation of cancer cells through altering promoter accessibility of target genes. Our study helps advance understanding of how cancer cells adapt to the stress induced by chemotherapy through TF binding motif accessibility.
    Keywords:  NSCLC; chemotherapy; chromatin accessibility; dormancy and reactivation; transcription factors
    DOI:  https://doi.org/10.1016/j.omtn.2021.07.019
  9. Front Oncol. 2021 ;11 710538
    Long Non-Coding RNAs as Potential Diagnostic and Prognostic Biomarkers in Breast Cancer: Progress and Prospects.
    Cuicui Lu, Duncan Wei, Yahui Zhang, Peng Wang, Wen Zhang.
      Breast cancer is the most common malignancy among women worldwide, excluding non-melanoma skin cancer. It is now well understood that breast cancer is a heterogeneous entity that exhibits distinctive histological and biological features, treatment responses and prognostic patterns. Therefore, the identification of novel ideal diagnostic and prognostic biomarkers is of utmost importance. Long non-coding RNAs (lncRNAs) are commonly defined as transcripts longer than 200 nucleotides that lack coding potential. Extensive research has shown that lncRNAs are involved in multiple human cancers, including breast cancer. LncRNAs with dysregulated expression can act as oncogenes or tumor-suppressor genes to regulate malignant transformation processes, such as proliferation, invasion, migration and drug resistance. Intriguingly, the expression profiles of lncRNAs tend to be highly cell-type-specific, tissue-specific, disease-specific or developmental stage-specific, which makes them suitable biomarkers for breast cancer diagnosis and prognosis.
    Keywords:  biomarker; breast cancer; diagnosis; long non-coding RNA; prognosis
    DOI:  https://doi.org/10.3389/fonc.2021.710538
  10. Neoplasma. 2021 Sep 17. pii: 210624N846. [Epub ahead of print]
    Recent advances in the contribution of circRNAs to cisplatin chemotherapy resistance in cancers.
    Chao Mu, Xiao-Lu Wang, Ying Ruan, Jia-Jia Sun, Xin-Rong Hu, Ying Cheng.
      Worldwide, cancer is a serious threat to the health of citizens of every country, with the incidence and mortality increasing year by year. Cisplatin is the first-line anticancer drug commonly used in clinics and is widely used for the treatment of solid tumors including lung, gastric, liver, bladder, and ovarian cancer. Although cisplatin-based chemotherapy has a high clinical response efficacy, patients will inevitably develop drug resistance after repeated using, leading to severe restrictions of its application. Circular RNAs (circRNAs) are a promising class of non-coding RNAs capable of promoting or suppressing cancer via functioning as miRNAs sponges. Recently, an increasing amount of evidence shows that circRNAs are closely related to the cisplatin resistance of cancers. Therefore, standing at the perspective of the cisplatin chemotherapy resistance, this paper reviews the research progress of circRNAs related to cisplatin resistance of various cancers.
    DOI:  https://doi.org/10.4149/neo_2021_210624N846
  11. Nucleic Acids Res. 2021 Sep 17. pii: gkab813. [Epub ahead of print]
    FACT-seq: profiling histone modifications in formalin-fixed paraffin-embedded samples with low cell numbers.
    Linxuan Zhao, Pengwei Xing, Vamsi Krishna Polavarapu, Miao Zhao, Blanca Valero-Martínez, Yonglong Dang, Nagaprathyusha Maturi, Lucy Mathot, Inês Neves, Irem Yildirim, Fredrik Johansson Swartling, Tobias Sjöblom, Lene Uhrbom, Xingqi Chen.
      The majority of biopsies in both basic research and translational cancer studies are preserved in the format of archived formalin-fixed paraffin-embedded (FFPE) samples. Profiling histone modifications in archived FFPE tissues is critically important to understand gene regulation in human disease. The required input for current genome-wide histone modification profiling studies from FFPE samples is either 10-20 tissue sections or whole tissue blocks, which prevents better resolved analyses. But it is desirable to consume a minimal amount of FFPE tissue sections in the analysis as clinical tissues of interest are limited. Here, we present FFPE tissue with antibody-guided chromatin tagmentation with sequencing (FACT-seq), the first highly sensitive method to efficiently profile histone modifications in FFPE tissues by combining a novel fusion protein of hyperactive Tn5 transposase and protein A (T7-pA-Tn5) transposition and T7 in vitro transcription. FACT-seq generates high-quality chromatin profiles from different histone modifications with low number of FFPE nuclei. We proved a very small piece of FFPE tissue section containing ∼4000 nuclei is sufficient to decode H3K27ac modifications with FACT-seq. H3K27ac FACT-seq revealed disease-specific super enhancers in the archived FFPE human colorectal and human glioblastoma cancer tissue. In summary, FACT-seq allows decoding the histone modifications in archival FFPE tissues with high sensitivity and help researchers to better understand epigenetic regulation in cancer and human disease.
    DOI:  https://doi.org/10.1093/nar/gkab813
  12. Prog Biophys Mol Biol. 2021 Sep 09. pii: S0079-6107(21)00101-2. [Epub ahead of print]
    The evolution of evolutionary processes in organismal and cancer evolution.
    Frank H Laukien.
      The evolution of early life and of contemporary viruses has been driven in significant part by random genetic mutations, while modern unicellular and organismal evolution primarily leverages evolved, efficient and active cell biology processes for adaptive changes prior to selection. Random mutations are often buffered by cell homeostasis, or they have a negative role, e.g., by causing death or monogenic diseases, or by triggering real-time cancer evolution. Accordingly, the Modern Synthesis theory no longer adequately describes the efficient, often punctuated and at times directionally adaptive natural genetic engineering (NGE) processes deduced from the DNA record of evolution. Similarly, the somatic mutation theory (SMT) of cancer describes driver mutations that can trigger oncogenesis, and passenger mutations characteristic of periods of genetic microevolution in cancer. At the precancerous stage, most somatic mutations are repaired or buffered in the cell, aberrant cells are removed, or organismal bioelectric tissue signals or other physiological functional networks maintain control of rogue, mutated cells. However, the SMT is not sufficient to describe the observed punctuated macroevolution of cancer-cell genes, chromosomes, karyotypes and epigenomes, nor of expressed cancer-cell transcriptomes, proteomes and epiproteomes, which include non-DNA-templated post-translational modifications, protein-protein interactions and metabolites. Moreover, punctuated cancer cell macroevolution often culminates in macro-effects, which include epithelial-mesenchymal transitions (EMT), cancer cell polyploidies and even giant multinucleated cancer cells that drive cancer progression, therapy resistance and metastasis. All of this cancer-cell evolution competes in a molecular and cellular arms race with host immune cells and antibodies, as well as with the host tumor microenvironment. Empirically observed punctuated, multilevel and multiclonal cancer macroevolution, and the concomitant, rapid co-development of the host immune system and tumor microenvironment, can occur with the efficiency, speed and lethality of cancer that is enabled by evolved, active natural genetic engineering (NGE) mechanisms. NGE affects both vertical cancer-cell genomic inheritance and evolution towards therapy resistance and metastasis, as well as viral or cancer-cell exosome vector-driven horizontal gene transfers that contributes to cancer cell cooperation, or to transforming previously non-cancerous somatic cells into destabilized cancer cells during metastasis. In addition, externally driven, irreversible and transferable (EDIT) adaptations are exemplified by mitotically heritable, non-templated cancer cell epigenetics, and by mitotically heritable cancer-cell surface protein and lipid glycosylation, as important examples of fast time-scale molecular evolution mechanisms in which genes are followers, similar to evo-devo processes in organismal evolution.
    Keywords:  Cancer evolution; Epiproteome; Evolvability; Glycosylation; Heritable adaptation processes
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2021.08.008
  13. Emerg Top Life Sci. 2021 Sep 13. pii: ETLS20210074. [Epub ahead of print]
    Single nucleus RNA-sequencing: how it's done, applications and limitations.
    Juliane Fischer, Thomas Ayers.
      Single nuclei RNA-sequencing (sNuc-Seq) is a methodology which uses isolated nuclei instead of whole cells to profile gene expression. By using droplet microfluidic technologies, users are able to profile thousands of single transcriptomes at high throughput from their chosen tissue. This article aims to introduce sNuc-Seq as a method and its utility in multiple tissue types. Furthermore, we discuss the risks associated with the use of nuclei, which must be considered before committing to a methodology.
    Keywords:  DroNc-Seq; NGS; sNuc-Seq; scRNA-Seq; single cell
    DOI:  https://doi.org/10.1042/ETLS20210074
  14. Mol Syst Biol. 2021 Sep;17(9): e10105
    Modeling glioblastoma heterogeneity as a dynamic network of cell states.
    Ida Larsson, Erika Dalmo, Ramy Elgendy, Mia Niklasson, Milena Doroszko, Anna Segerman, Rebecka Jörnsten, Bengt Westermark, Sven Nelander.
      Tumor cell heterogeneity is a crucial characteristic of malignant brain tumors and underpins phenomena such as therapy resistance and tumor recurrence. Advances in single-cell analysis have enabled the delineation of distinct cellular states of brain tumor cells, but the time-dependent changes in such states remain poorly understood. Here, we construct quantitative models of the time-dependent transcriptional variation of patient-derived glioblastoma (GBM) cells. We build the models by sampling and profiling barcoded GBM cells and their progeny over the course of 3 weeks and by fitting a mathematical model to estimate changes in GBM cell states and their growth rates. Our model suggests a hierarchical yet plastic organization of GBM, where the rates and patterns of cell state switching are partly patient-specific. Therapeutic interventions produce complex dynamic effects, including inhibition of specific states and altered differentiation. Our method provides a general strategy to uncover time-dependent changes in cancer cells and offers a way to evaluate and predict how therapy affects cell state composition.
    Keywords:  cell state; cellular barcoding; patient-derived brain tumor cells; single-cell lineage tracing; time-dependent computational models
    DOI:  https://doi.org/10.15252/msb.202010105
  15. Clin Cancer Res. 2021 Sep 15. pii: clincanres.4796.2020. [Epub ahead of print]
    Single-cell analyses reveal mechanisms of cancer stem cell maintenance and epithelial-mesenchymal transition in recurrent bladder cancer.
    Huanjun Wang, Yan Mei, Cheng Luo, Qun Huang, Zifeng Wang, Guan-Ming Lu, Lili Qin, Zhun Sun, Chao-Wen Huang, Zhi-Wen Yang, Junxing Chen, Weiguo Yin, Chao-Nan Qian, Jianming Zeng, Lingwu Chen, Qibin Leng, Yan Guo, Guangshuai Jia.
       PURPOSE: Bladder cancer (BC) treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of BC recurrence.
    EXPERIMENTAL DESIGN: Here, we performed single-cell RNA-seq and ATAC-seq on tumors from 13 patients with low recurrence risk, high recurrence risk and recurrent BC.
    RESULTS: Our study generated a comprehensive cancer cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem cell subpopulation is enriched during BC recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial-mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with BC subtypes. We identified that TCF7 promotes EMT in corroboration with scATAC-seq analysis. Additionally, we constructed regulatory networks specific to recurrent BC.
    CONCLUSIONS: Our study and analytical approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the BC research field.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4796
  16. Anal Chem. 2021 Sep 14.
    Investigating Lysosomal Autophagy via Surface-Enhanced Raman Scattering Spectroscopy.
    Jing Yue, Yanting Shen, Chongyang Liang, Wei Shi, Weiqing Xu, Shuping Xu.
      Autophagy plays a critical role in many vitally important physiological and pathological processes, such as the removal of damaged and aged organelles and redundant proteins. Although autophagy is mainly a protective process for cells, it can also cause cell death. In this study, we employed in situ and ex situ surface-enhanced Raman scattering (SERS) spectroscopies to obtain chemical information of lysosomes of HepG2 cells. Results reveal that the SERS profiles of the isolated lysosomes are different from the in situ spectra, indicating that lysosomes lie in different microenvironments in these two cases. We further investigated the molecular changes of isolated lysosomes according to the autophagy induced by starvation via ex situ SERS. During autophagy, the conformation of proteins and the structures of lipids have been affected, and autophagy-related molecular evidence is given for the first time in the living lysosomes. We expect that this study will provide a reference for understanding the cell autophagy mechanism.
    DOI:  https://doi.org/10.1021/acs.analchem.1c02939
  17. Int J Biol Sci. 2021 ;17(13): 3493-3507
    Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro.
    Miao Bai, Mengqi Cui, Mingyue Li, Xinlei Yao, Yulun Wu, Lihua Zheng, Luguo Sun, Qiuhang Song, Shuyue Wang, Lei Liu, Chunlei Yu, Yanxin Huang.
      Histone deacetylases (HDACs) exhibit increased expression in cancer and promote oncogenesis via the acetylation of or interactions with key transcriptional regulators. HDAC inhibitors (HDACis) decrease HDAC activity to selectively inhibit the occurrence and development of tumors. Our study screened and obtained a new HDACi structure. In vitro experiments have showed that among the leads, Z31216525 significantly inhibited the proliferation and induced the apoptosis of epithelial ovarian cancer (EOC) cells. In vivo experiments demonstrated that compared to the control, Z31216525 significantly inhibited tumor growth and showed very low toxicity. Further mechanistic studies revealed that Z31216525 may exert an antitumor effect by inhibiting the expression of the c-Myc gene. Collectively, our studies identified a novel HDACi that is expected to become a new potential therapeutic drug for EOC and has important value for the design of new HDACi structures.
    Keywords:  EOC; HDAC7; HDACi; c-Myc
    DOI:  https://doi.org/10.7150/ijbs.62339
  18. Brief Bioinform. 2021 Sep 15. pii: bbab378. [Epub ahead of print]
    How much can deep learning improve prediction of the responses to drugs in cancer cell lines?
    Yurui Chen, Louxin Zhang.
      The drug response prediction problem arises from personalized medicine and drug discovery. Deep neural networks have been applied to the multi-omics data being available for over 1000 cancer cell lines and tissues for better drug response prediction. We summarize and examine state-of-the-art deep learning methods that have been published recently. Although significant progresses have been made in deep learning approach in drug response prediction, deep learning methods show their weakness for predicting the response of a drug that does not appear in the training dataset. In particular, all the five evaluated deep learning methods performed worst than the similarity-regularized matrix factorization (SRMF) method in our drug blind test. We outline the challenges in applying deep learning approach to drug response prediction and suggest unique opportunities for deep learning integrated with established bioinformatics analyses to overcome some of these challenges.
    Keywords:  convolutional neural networks; deep learning; drug response prediction; graph neural networks
    DOI:  https://doi.org/10.1093/bib/bbab378
  19. Comput Biol Med. 2021 Sep 08. pii: S0010-4825(21)00645-4. [Epub ahead of print]137 104851
    In silico methods and tools for drug discovery.
    Bilal Shaker, Sajjad Ahmad, Jingyu Lee, Chanjin Jung, Dokyun Na.
      In the past, conventional drug discovery strategies have been successfully employed to develop new drugs, but the process from lead identification to clinical trials takes more than 12 years and costs approximately $1.8 billion USD on average. Recently, in silico approaches have been attracting considerable interest because of their potential to accelerate drug discovery in terms of time, labor, and costs. Many new drug compounds have been successfully developed using computational methods. In this review, we briefly introduce computational drug discovery strategies and outline up-to-date tools to perform the strategies as well as available knowledge bases for those who develop their own computational models. Finally, we introduce successful examples of anti-bacterial, anti-viral, and anti-cancer drug discoveries that were made using computational methods.
    Keywords:  Computational drug discovery; Computer-aided drug design; Target identification; Toxicity prediction; Virtual screening
    DOI:  https://doi.org/10.1016/j.compbiomed.2021.104851
  20. Cancer Manag Res. 2021 ;13 6879-6889
    MALAT-1 is Associated with the Doxorubicin Resistance in U-2OS Osteosarcoma Cells.
    Chang Liu, Xuesong Han, Bo Li, Shaobin Huang, Zhong Zhou, Zhiwei Wang, Wanming Wang.
       Purpose: Our study aimed to investigate the relationship between MALAT-1 (metastasis-associated lung adenocarcinoma transcript 1) expression and the chemotherapy drug resistance in osteosarcoma.
    Methods: The U-2OS osteosarcoma cell line was selected for the experiment. The cells were treated with methotrexate, doxorubicin, cisplatin, and ifosfamide, respectively. RT-PCR was applied to detect the MALAT-1 expression in cells. The doxorubicin-resistant cell line was constructed. The cells were divided into doxorubicin-sensitivity group (DS/shCtrl), doxorubicin-resistance group (DR/shCtrl) and shMALAT1-doxorubicin-resistance group (DR/shMALAT1). The colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to detect cell proliferation. PI staining was used to detect the cell cycle. Transwell assay and wound healing assay were used to observe the migration and invasion ability. Annexin V-FITC assay was used to detect cell apoptosis. Western blot was used to detect the protein expression and potential mechanism. The impacts of MALAT-1 expression were verified in vivo.
    Results: The MALAT-1 was upregulated in the doxorubicin-resistant U-2OS osteosarcoma cells. Downregulating MALAT-1 in the doxorubicin-resistant cells inhibited the proliferation, migration, and invasiveness, increased the ratio of cells in the G0/G1 phase, promoted apoptosis. In the doxorubicin-resistant U-2OS cells, the extracellular regulated protein kinases (ERK) phosphorylation was declined, which could be reversed by downregulating MALAT-1. In vivo assay indicated that the growth of doxorubicin-resistant solid osteosarcoma could be suppressed by downregulating MALAT-1.
    Conclusion: Our study provides evidence that doxorubicin may upregulate MALAT-1 in osteosarcoma. Downregulating MALAT-1 in the doxorubicin resistance U-2OS cells could reverse the resistance and may improve chemotherapeutic efficiency. Some conclusions in previous literature may be one-sided.
    Keywords:  MALAT-1; chemotherapy resistance; doxorubicin; extracellular regulated protein kinases; long noncoding RNA; osteosarcoma
    DOI:  https://doi.org/10.2147/CMAR.S304922
  21. J Cell Physiol. 2021 Sep 14.
    Dynamic alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged-1 gene promoters cause an inflammatory switch of endothelial cells.
    Yash T Katakia, Niyati P Thakkar, Sumukh Thakar, Ashima Sakhuja, Raghav Goyal, Harshita Sharma, Rakshita Dave, Ayushi Mandloi, Sayan Basu, Ishan Nigam, Bhanu V R Kuncharam, Shibasish Chowdhury, Syamantak Majumder.
      Histone protein modifications control the inflammatory state of many immune cells. However, how dynamic alteration in histone methylation causes endothelial inflammation and apoptosis is not clearly understood. To examine this, we explored two contrasting histone methylations; an activating histone H3 lysine 4 trimethylation (H3K4me3) and a repressive histone H3 lysine 27 trimethylation (H3K27me3) in endothelial cells (EC) undergoing inflammation. Through computer-aided reconstruction and 3D printing of the human coronary artery, we developed a unique model where EC were exposed to a pattern of oscillatory/disturbed flow as similar to in vivo conditions. Upon induction of endothelial inflammation, we detected a significant rise in H3K4me3 caused by an increase in the expression of SET1/COMPASS family of H3K4 methyltransferases, including MLL1, MLL2, and SET1B. In contrast, EC undergoing inflammation exhibited truncated H3K27me3 level engendered by EZH2 cytosolic translocation through threonine 367 phosphorylation and an increase in the expression of histone demethylating enzyme JMJD3 and UTX. Additionally, many SET1/COMPASS family of proteins, including MLL1 (C), MLL2, and WDR5, were associated with either UTX or JMJD3 or both and such association was elevated in EC upon exposure to inflammatory stimuli. Dynamic enrichment of H3K4me3 and loss of H3K27me3 at Notch-associated gene promoters caused ADAM17 and Jagged-1 derepression and abrupt Notch activation. Conversely, either reducing H3K4me3 or increasing H3K27me3 in EC undergoing inflammation attenuated Notch activation, endothelial inflammation, and apoptosis. Together, these findings indicate that dynamic chromatin modifications may cause an inflammatory and apoptotic switch of EC and that epigenetic reprogramming can potentially improve outcomes in endothelial inflammation-associated cardiovascular diseases.
    Keywords:  3D printing; Notch signaling; endothelial cell; histone methylation; inflammation
    DOI:  https://doi.org/10.1002/jcp.30579
  22. J Gastrointest Oncol. 2021 Aug;12(4): 1601-1612
    Effects of YAP1 and SFRP2 overexpression on the biological behavior of colorectal cancer cells and their molecular mechanisms.
    Zhenzhen Bai, Qingqing Wu, Cong Zhang, Jing Chen, Liyu Cao.
       Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and has a high mortality rate. With the development of tumor molecular biology, more and more attention is being paid to the mechanisms of cell pathways in colorectal carcinogenesis, such as the Hippo/Yes-associated protein 1 (YAP1) and Wnt/β-catenin signaling pathways. The abnormal expression of YAP1 and β-catenin have been reported in CRC, and can lead to excessive cell proliferation, and eventually, tumor formation. Secreted frizzled-related protein 2 (SFRP2) levels have been found to be decreased in a variety of cancers, and SFRP2 is an antagonist that binds directly to Wnt signal. At present, the molecular basis of colorectal tumors is still not fully understood. In the present study, we sought to identify the molecular mechanisms underlying YAP1 and SFRP2 in the development of CRC.
    Methods: We constructed CRC cell lines that stably overexpressed YAP1 and SFRP2 using lentivirus packaging and cell infection. The levels of expression of the proteins were evaluated by western blot and immunofluorescence assays. Protein complex immunoprecipitation (Co-IP) was used to detect the interaction between YAP1, SFRP2, and β-catenin. The functional roles of YAP1 and SFRP2 in CRC was determined by a Cell Counting Kit-8 (CCK8) proliferation assay and flow cytometric apoptosis assay.
    Results: The data of the present study showed that the overexpression of SFRP2 promoted the expression of YAP1 and β-catenin protein, and the overexpression of YAP1 promoted the expression of β-catenin protein. YAP1 overexpression promoted cell proliferation, while SFRP2 overexpression inhibited cell proliferation and promoted cell apoptosis.
    Conclusions: Our findings showed that the expression of YAP1, SFRP2, and β-catenin is correlated in CRC cells. The Hippo pathway and Wnt pathway interact with each other in the pathogenesis of CRC, and YAP1 and SFRP2 are involved in the formation and development of CRC.
    Keywords:  Yes-associated protein 1 (YAP1); colorectal cancer (CRC); secreted frizzled-related protein 2 (SFRP2); β-catenin
    DOI:  https://doi.org/10.21037/jgo-21-418
  23. Int J Biol Sci. 2021 ;17(13): 3634-3645
    Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.
    Ting Sun, Hui Peng, Wenhao Mao, Liwei Ma, Hongyang Liu, Jia Mai, Lin Jiao.
      Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.
    Keywords:  Atg5; YAP; autophagy; pancreatic cancer; verteporfin
    DOI:  https://doi.org/10.7150/ijbs.61795
  24. Front Cell Dev Biol. 2021 ;9 705291
    Autophagy-Related Genes and Long Noncoding RNAs Signatures as Predictive Biomarkers for Osteosarcoma Survival.
    Jian Zhang, Rui Ding, Tianlong Wu, Jingyu Jia, Xigao Cheng.
      Osteosarcoma is a common malignant tumor that seriously threatens the lives of teenagers and children. Autophagy is an intracellular metabolic process mediated by autophagy-related genes (ARGs), which is known to be associated with the progression and drug resistance of osteosarcoma. In this study, RNA sequence data from TARGET and genotype-tissue expression (GTEx) databases were analyzed. A six autophagy-related long noncoding RNAs (ARLs) signature that accurately predicted the clinical outcomes of osteosarcoma patients was identified, and the relations between immune response and the ARLs prognostic signature were examined. In addition, we obtained 30 ARGs differentially expressed among osteosarcoma tissue and healthy tissue, and performed functional enrichment analysis on them. To screen for prognostic-related ARGs, univariate and LASSO Cox regression analyses were successively applied. Then, multivariate regression analysis was used to complete construction of the prognostic signature of ARGs. Based on the risk coefficient, we calculated the risk score and grouped the patients. Survival analysis showed that high-risk patients evolve with poor prognosis. And we verified the prognosis model in the GSE21257 cohort. Finally, verification was conducted by qRT-PCR and western blot to measure the expression of genes. The results show that autophagy-related marker models may provide a new therapeutic and diagnostic target for osteosarcoma.
    Keywords:  autophagy; biomarkers; lncRNA; osteosarcoma; prognostic signature
    DOI:  https://doi.org/10.3389/fcell.2021.705291
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