bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒10‒16
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Cancer: More than a geneticist's Pandora's box.
  2. Recognition of stapled histone H3K4me3 peptides by epigenetic reader proteins.
  3. Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells.
  4. Quantification of mechanical stimuli inducing nucleoplasmic translocation of YAP and its distribution mechanism using an AFM-dSTORM coupled technique.
  5. Drugging p53 in cancer: one protein, many targets.
  6. Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment.
  7. Decoding the colorectal cancer ecosystem emphasizes the cooperative role of cancer cells, TAMs and CAFsin tumor progression.
  8. Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer.
  9. Mechanosensitive Ion Channel PIEZO1 Signaling in the Hall-Marks of Cancer: Structure and Functions.
  1. J Biosci. 2022 ;pii: 21. [Epub ahead of print]47
    Cancer: More than a geneticist's Pandora's box.
    Kritika Saxena, Ayalur Raghu Subbalakshmi, Prakash Kulkarni, Mohit Kumar Jolly.
      Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as nongenetic/ non-mutational heterogeneity. Such heterogeneity - a ubiquitous nature of biological systems - has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systemslevel approach integrating mathematical modeling and in (vitro/in vivo) experiments can map the diverse phenotypic repertoire and identify therapeutic vulnerabilities of an otherwise clonal cell population.
  2. Chem Commun (Camb). 2022 Oct 14.
    Recognition of stapled histone H3K4me3 peptides by epigenetic reader proteins.
    Peter Betlem, Marijn N Maas, Jim Middelburg, Bas J G E Pieters, Jasmin Mecinović.
      The flexible N-terminal histone tails are a subject of numerous posttranslational modifications, including methylation. We report development of stapled histone peptides bearing trimethyllysine as ligands for epigenetic reader proteins. Stronger or weaker binding affinities have been observed for stapled histone peptides relative to linear histones, indicating that selectivity towards reader proteins can be achieved.
    DOI:  https://doi.org/10.1039/d2cc04294k
  3. Cancers (Basel). 2022 Oct 04. pii: 4845. [Epub ahead of print]14(19):
    Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells.
    Jin Seok Hwang, Trang Huyen Lai, Mahmoud Ahmed, Trang Minh Pham, Omar Elashkar, Entaz Bahar, Deok Ryong Kim.
      Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy's involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF-β1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of BECN1 or chloroquine (CQ) treatment inhibited mesenchymal protein expression. Interestingly, TGF-β1 promoted the transcription of target mRNAs, SNAI1, VIM, and CDH2, regardless of autophagy status. The imbalance between protein and mRNA levels indicated the possibility of autophagy-dependent translational regulation. Since protein synthesis consumes large amounts of energy, it is tightly regulated via various cellular signaling pathways such as AMPK and mTOR. Our investigation showed inhibition of autophagy decreased ATP production from OXPHOS and led to the suppression of mRNA translation by phosphorylation of eukaryotic elongation factor 2 (eEF2). These results suggest that A549 non-small cell lung cancer required autophagy to maintain mitochondrial homeostasis during TGF-β1 induced EMT. In conclusion, blocking autophagy decreased energy production and down-regulated proteins synthesis inhibiting TGF-β1 induced EMT.
    Keywords:  A549 cells; EMT; TGF-β1; autophagy; energy metabolism
    DOI:  https://doi.org/10.3390/cancers14194845
  4. Nanoscale. 2022 Oct 13.
    Quantification of mechanical stimuli inducing nucleoplasmic translocation of YAP and its distribution mechanism using an AFM-dSTORM coupled technique.
    Hongru Li, Yong Liu, Jinrui Zhang, Mingjun Cai, Ziran Cao, Jing Gao, Haijiao Xu, Lina Shao, Jiayin Sun, Yan Shi, Hongda Wang.
      Cells can regulate a variety of behaviors by sensing mechanical signals, including growth, differentiation, apoptosis and so on. Yes-associated protein (YAP) is a mechanically sensitive protein that can be used as an indicator of mechanosignaling transduction. Unlike macroscopic statistical analysis, single-cell analysis is more demanding and challenging in terms of mechanistic regulation. Here, we quantified the location, amplitude and duration of single-cell mechanical stimulation by precise mechanical modulation, and simultaneously observed the mechanical force induced YAP nuclear and cytoplasmic distribution translocation using the AFM-dSTORM coupled techniques. Additionally, we investigated the regulation of YAP translocation according to the physical factors (cytoskeletal destruction and osmotic pressure) and biochemical factors (nuclear active transport protein inhibiter and starvation). Our study revealed that mechanical signals were transferred from the cytoskeleton to the nucleus through the synergistic action of microfilaments and microtubules, and then induced YAP translocation from the nucleus to the cytoplasm under the cooperation of nuclear export proteins. This conclusion deepens the understanding of the signaling pathway by which mechanical signals are transmitted from the plasma membrane to the cytoplasm and then to the nucleus to determine the cell's fate.
    DOI:  https://doi.org/10.1039/d2nr03366f
  5. Nat Rev Drug Discov. 2022 Oct 10.
    Drugging p53 in cancer: one protein, many targets.
    Ori Hassin, Moshe Oren.
      Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.
    DOI:  https://doi.org/10.1038/s41573-022-00571-8
  6. Cancers (Basel). 2022 Sep 20. pii: 4544. [Epub ahead of print]14(19):
    Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment.
    Cassidy M Van Stiphout, Anita K Luu, Alicia M Viloria-Petit.
      Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing secondary/metastatic tumors. The molecular complexity of tumor metastasis and the lack of effective therapies for OS has cultivated interest in exploiting the proteasome as a molecular target for anti-cancer therapy. As our understanding towards the behavior of malignant cells expands, it is evident that cancerous cells display a greater reliance on the proteasome to maintain homeostasis and sustain efficient biological activities. This led to the development and approval of first- and second-generation proteasome inhibitors (PIs), which have improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Researchers have since postulated the therapeutic potential of PIs for the treatment of OS. As such, this review aims to summarize the biological effects and latest findings from clinical trials investigating PI-based treatments for OS. Integrating PIs into current treatment regimens may better outcomes for patients diagnosed with OS.
    Keywords:  bortezomib; carfilzomib; ixazomib; osteosarcoma; proteasome inhibitors; targeted therapy
    DOI:  https://doi.org/10.3390/cancers14194544
  7. J Transl Med. 2022 Oct 08. 20(1): 462
    Decoding the colorectal cancer ecosystem emphasizes the cooperative role of cancer cells, TAMs and CAFsin tumor progression.
    Rongfang Shen, Ping Li, Botao Zhang, Lin Feng, Shujun Cheng.
      BACKGROUND: Single-cell transcription data provided unprecedented molecular information, enabling us to directly encode the ecosystem of colorectal cancer (CRC). Characterization of the diversity of epithelial cells and how they cooperate with tumor microenvironment cells (TME) to endow CRC with aggressive characteristics at single-cell resolution is critical for the understanding of tumor progression mechanism.METHODS: In this study, we comprehensively analyzed the single-cell transcription data, bulk-RNA sequencing data and pathological tissue data. In detail, cellular heterogeneity of TME and epithelial cells were analyzed by unsupervised classification and consensus nonnegative matrix factorization analysis, respectively. Functional status of epithelial clusters was annotated by CancerSEA and its crosstalk with TME cells was investigated using CellPhoneDB and correlation analysis. Findings from single-cell transcription data were further validated in bulk-RNA sequencing data and pathological tissue data.
    RESULTS: A distinct cellular composition was observed between tumor and normal tissues, and tumors exhibited immunosuppressive phenotypes. Regarding epithelial cells, we identified one highly invasiveQuery cluster, C4, that correlated closely with tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). Further analysis emphasized the TAMs subclass TAM1 and CAFs subclass S5 are closely related with C4.
    CONCLUSIONS: In summary, our study elaborates on the cellular heterogeneity of CRC, revealing that TAMs and CAFs were critical for crosstalk network epithelial cells and TME cells. This in-depth understanding of cancer cell-TME network provided theoretical basis for the development of new drugs targeting this sophisticated network in CRC.
    Keywords:  Cancer-associated fibroblasts; Colorectal cancer; Epithelium-microenvironment communication; Tumor heterogeneity; Tumor-associated macrophages; scRNA-seq
    DOI:  https://doi.org/10.1186/s12967-022-03661-8
  8. Cancer Cell Int. 2022 Oct 13. 22(1): 316
    Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer.
    Omnia Emam, Eman F Wasfey, Nadia M Hamdy.
      BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent digestive cancers, ranking the 2nd cause of cancer-related fatality worldwide. The worldwide burden of CRC is predicted to rise by 60% by 2030. Environmental factors drive, first, inflammation and hence, cancer incidence increase. MAIN: The Notch-signaling system is an evolutionarily conserved cascade, has role in the biological normal developmental processes as well as malignancies. Long non-coding RNAs (LncRNAs) have become major contributors in the advancement of cancer by serving as signal pathways regulators. They can control gene expression through post-translational changes, interactions with micro-RNAs or down-stream effector proteins. Recent emerging evidence has emphasized the role of lncRNAs in controlling Notch-signaling activity, regulating development of several cancers including CRC.CONCLUSION: Notch-associated lncRNAs might be useful prognostic biomarkers or promising potential therapeutic targets for CRC treatment. Therefore, here-in we will focus on the role of "Notch-associated lncRNAs in CRC" highlighting "the impact of Notch-associated lncRNAs as player for cancer induction and/or progression."
    Keywords:  Colorectal cancer; Epigenetics; Hallmarks of cancer; Inflammation; Micro-RNAs; Notch; lncRNAs
    DOI:  https://doi.org/10.1186/s12935-022-02736-2
  9. Cancers (Basel). 2022 Oct 10. pii: 4955. [Epub ahead of print]14(19):
    Mechanosensitive Ion Channel PIEZO1 Signaling in the Hall-Marks of Cancer: Structure and Functions.
    Fuqiang Zhao, Lei Zhang, Mankun Wei, Wei Duan, Shourong Wu, Vivi Kasim.
      Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties. Cells in tumor tissue sense mechanical signals from the tumor microenvironment, which consequently drive the acquisition of hallmarks of cancer, including sustained proliferative signaling, evading growth suppressors, apoptosis resistance, sustained angiogenesis, metastasis, and immune evasion. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanically sensitive ion channel protein that can be activated mechanically and is closely related to various diseases. Recent studies showed that Piezo1 mediates tumor development through multiple mechanisms, and its overexpression is associated with poor prognosis. Therefore, the discovery of Piezo1, which links-up physical factors with biological properties, provides a new insight for elucidating the mechanism of tumor progression under a mechanical microenvironment, and suggests its potential application as a tumor marker and therapeutic target. In this review, we summarize current knowledge regarding the role of Piezo1 in regulating cancer hallmarks and the underlying molecular mechanisms. Furthermore, we discuss the potential of Piezo1 as an antitumor therapeutic target and the limitations that need to be overcome.
    Keywords:  Piezo1; hallmarks of cancer; ion channel; mechanical signals; tumorigenesis
    DOI:  https://doi.org/10.3390/cancers14194955
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