bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒03‒26
fourteen papers selected by
Ankita Daiya
BITS Pilani

  1. Pol J Pathol. 2022 ;pii: 50228. [Epub ahead of print]73(4): 343-351
      Osteosarcoma (OS) is the most common malignant bone tumour; however, the underlying mechanisms are mainly unknown. Enhancer of zeste homologue 2 (EZH2) and NOTCH pathway are important molecular signals related to carcinogenesis and tumour progression, but they are not fully understand in OS. Enhancer of zeste homologue 2, Notch3, HES1, and Nanog were detected on OS samples and statistically analysed. Expressions of these genes were investigate, and stem-like phenotype was verified in OS cells. This study found that higher EZH2 expression, Notch3 pathway, or Nanog were associated with tumour relapse and metastasis and a significantly shorter survival time. Moreover, the Notch3 pathway was activated in osteosarcoma stem cells. Enhancer of zeste homologue 2 overexpression could activate the Notch3 pathway and increase HES1 expression, leading to upregulated stem cell-related gene expression and self-renewal of OS cells. Our study demonstrates that EZH2, Notch3, and Nanog are important prognostic factors. Enhancer of zeste homologue 2 could maintain the self-renewal of OS cells, where the Notch3 pathway activation may be involved.
    Keywords:   EZH2; Nanog; Notch3; osteosarcoma
  2. Macromol Biosci. 2023 Mar 21. e2300053
      Polyrotaxane is a supramolecular assembly consisting of multiple cyclic molecules threaded by a linear polymer. One of the unique properties of polyrotaxane is the molecular mobility, cyclic molecules moving along the linear polymer. Molecular mobility of polyrotaxane surfaces affect cell spreading, differentiation, and other cell-related aspects through changing subcellular localization of yes-associated proteins (YAPs). Subcellular YAP localization is also related to cell senescence derived from oxidative stress, which is known to cause cancer, diabetes, and heart disease. Here, the effects of polyrotaxane surface molecular mobility on subcellular YAP localization and cell senescence following H2 O2 -induced oxidative stress have been evaluated in human mesenchymal stem cells (HMSCs) cultured on polyrotaxane surfaces with different molecular mobilities. Oxidative stress promotes cytoplasmic YAP localization in HMSCs on high-mobility polyrotaxane surfaces; however, low-mobility polyrotaxane surfaces more effectively maintain nuclear YAP localization, exhibiting lower senescence-associated β-galactosidase activity and senescence-related gene expression and DNA damage than that seen with the high-mobility surfaces. These results suggest that the molecular mobility of polyrotaxane surfaces regulates subcellular YAP localization, thereby protecting HMSCs from oxidative stress-induced cell senescence. Applying the molecular mobility of polyrotaxane surfaces to implantable scaffolds can provide insights into the prevention and treatment of diseases caused by oxidative stress. This article is protected by copyright. All rights reserved.
    Keywords:  cell senescence; molecular mobility; oxidative stress; polyrotaxane; yes-associated protein
  3. bioRxiv. 2023 Mar 07. pii: 2023.03.06.531456. [Epub ahead of print]
      Ehrlichia chaffeensis TRP120 effector has evolved short linear motif (SLiM) ligand mimicry to repurpose multiple evolutionarily conserved cellular signaling pathways including Wnt, Notch and Hedgehog. In this investigation, we demonstrate that E. chaffeensis and recombinant TRP120 deactivate Hippo signaling resulting in activation of Hippo transcription coactivator Yap and target gene expression. Moreover, a homologous 6 amino acid (QDVASH) SLiM shared by TRP120 and Wnt3a/5a ligands phenocopied Yap and β-catenin activation induced by E. chaffeensis, rTRP120 and Wnt5a. Similar Hippo gene expression profiles were also stimulated by E. chaffeensis, rTRP120, SLiM and Wnt5a. Single siRNA knockdown of Hippo transcription co-activator/factors (Yap and TEAD) significantly decreased E. chaffeensis infection. Yap activation was abolished in THP-1 Wnt Frizzled-5 (Fzd5) receptor knockout cells (KO), demonstrating Fzd5 receptor dependence. In addition, TRP120 Wnt-SLiM antibody blocked Hippo deactivation (Yap activation). Expression of anti-apoptotic Hippo target gene SLC2A1 (encodes glucose transporter 1; GLUT1) was upregulated by E. chaffeensis and corresponded to increased levels of GLUT1. Conversely, siRNA knockdown of SLC2A1 significantly inhibited infection. Higher GLUT1 levels correlated with increased BCL-xL and decreased Bax levels. Moreover, blocking Yap activation with the inhibitor Verteporfin induced apoptosis that corresponded to significant reductions in levels of GLUT1 and BCL-xL, and activation of Bax and Caspase-3 and -9. This study identifies a novel shared Wnt/Hippo SLiM ligand mimetic and demonstrates that E. chaffeensis deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis.
  4. Cancer Lett. 2023 Mar 21. pii: S0304-3835(23)00094-0. [Epub ahead of print] 216143
      Epigenetic modifications regulate critical biological processes that play a pivotal role in the pathogenesis of cancer. Enhancer of Zeste Homolog 2 (EZH2), a subunit of the Polycomb-Repressive Complex 2, catalyzes trimethylation of histone H3 on Lys 27 (H3K27) involved in gene silencing. EZH2 is amplified in human cancers and has roles in regulating several cellular processes, including survival, proliferation, invasion, and self-renewal. Though EZH2 is responsible for gene silencing through its canonical role, it also regulates the transcription of several genes promoting carcinogenesis via its non-canonical role. Constitutive activation of Nuclear Factor-kappaB (NF-κB) plays a crucial role in the development and progression of human malignancies. NF-κB is essential for regulating innate and adaptive immune responses and is one of the most important molecules that increases survival during carcinogenesis. Given the evidence that increased survival and proliferation are essential for tumor development and their association with epigenetic modifications, it seems plausible that EZH2 and NF-κB crosstalk may promote cancer progression. In this review, we expand on how EZH2 and NF-κB regulate cellular responses during cancer and their crosstalk of the canonical and non-canonical roles in a context-dependent manner.
    Keywords:  Cancer; Enhancer of zeste homolog 2; Inflammation; Nuclear Factor-kappaB; Polycomb-repressive complex 2
  5. Cancer Res. 2023 03 22. OF1-OF19
    TuPro Consortium
      Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers.SIGNIFICANCE: Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors.
  6. Acta Biochim Biophys Sin (Shanghai). 2023 Mar 25.
      Evolutionarily conserved, the Hippo signaling pathway is critical in regulating organ size and tissue homeostasis. The activity of this pathway is tightly regulated under normal circumstances, since its physical function is precisely maintained to control the rate of cell proliferation. Failure of maintenance leads to a variety of tumors. Our understanding of the mechanism of Hippo dysregulation and tumorigenesis is becoming increasingly precise, relying on the emergence of upstream inhibitor or activator and the connection linking Hippo target genes, mutations, and related signaling pathways with phenotypes. In this review, we summarize recent reports on the signaling network of the Hippo pathway in tumorigenesis and progression by exploring its critical mechanisms in cancer biology and potential targeting in cancer therapy.
    Keywords:  Hippo; TAZ; TEAD; YAP; cancer; hallmark; signal transduction
  7. bioRxiv. 2023 Mar 08. pii: 2023.03.08.531771. [Epub ahead of print]
      Histone H3 lysine 9 methylation (H3K9me) epigenetically silences gene expression by forming heterochromatin. Proteins called HP1, which contain specialized reader domains, bind to H3K9me and recruit factors that regulate epigenetic silencing. Though these interactions have been identified in vitro , we do not understand how HP1 proteins specifically and selectively bind to heterochromatin-associated factors within the nucleus. Using fission yeast as a model system, we measured the single-molecule dynamics associated with two archetypal HP1 paralogs, Swi6 and Chp2, and inferred how they form complexes with their interacting partners: Epe1, a putative H3K9 demethylase; Clr3, a histone deacetylase; and Mit1, a chromatin remodeler. Through a series of genetic perturbations that affect H3K9 methylation and HP1-mediated recruitment, we were able to track altered diffusive properties associated with each HP1 protein and its binding partner. Our findings show that the HP1-interacting proteins we investigated only co-localize with Swi6 and Chp2 at sites of H3K9me. When H3K9me is absent, Epe1 and Swi6 exhibit diffusive states consistent with off-chromatin interactions. Our results suggest that histone modifications like H3K9 methylation are not simply inert binding platforms but rather, they can shift the balance of HP1 complex assembly toward a predominantly chromatin-bound state. By inferring protein-protein interactions based on the altered mobilities of proteins in living cells, we propose that H3K9 methylation can stimulate the assembly of diverse HP1-associated complexes on chromatin.SIGNIFICANCE STATEMENT: During differentiation, epigenetic silencing is essential for preserving cellular identity. Establishing and maintaining epigenetic silencing depends on histone H3 lysine 9 methylation, which HP1 proteins recognize and bind with low micromolar affinity and millisecond-scale kinetics. HP1 proteins also recruit diverse histone modifiers to maintain gene silencing. HP1 protein biochemistry has revealed what can happen, but the state-of-the-art in this field includes little about what does happen in the complex and crowded environment of the nucleus. Using single-molecule tracking of HP1 proteins and their binding partners, we identified the rules that govern their complex formation in the native chromatin context, and we found that chromatin- previously thought to be an inert platform-enhances complex formation between HP1 and its binding partners.
  8. Oncol Lett. 2023 Apr;25(4): 144
      Malignant osteosarcoma (OS) is a tumor of bone and soft tissue that metastasizes early and has a high mortality rate. Protein serine kinase H1 (PSKH1), an autophosphorylating human protein serine kinase, controls the trafficking of serine/arginine-rich domain, with downstream effects on mRNA processing. It is also associated with tumor progression. However, how this protein contributes to OS progression and metastasis is unknown. The present study evaluated the potential effect of PSKH1 on proliferation of human OS cells. OS cell lines were used in Cell Counting Kit-8, colony formation, wound-healing and Transwell assays, to investigate cellular processes such as proliferation, migration and invasion and underlying molecular mechanisms. Expression of PSKH1 in OS tissue was significantly greater than in adjacent non-malignant tissue. PSKH1 knockdown inhibited the proliferation, migration and invasion of OS cells. Conversely, PSKH1 overexpression promoted proliferation of OS cells. PSKH1 upregulated phosphorylated-p38 in OS cells. Moreover, the p38 MAPK inhibitor SB203580 effectively blocked the tumor-promoting action of PSKH1. Furthermore, PSKH1 knockdown inhibited tumor growth and metastasis in vivo. In conclusion, these findings suggested that PSKH1 promoted OS proliferation, migration and invasion. Thus, PSKH1 may serve an oncogenic role in the development of human OS.
    Keywords:  cell invasion; cell proliferation; osteosarcoma; p38; protein serine kinase H1; therapeutic target
  9. Cancer Res Treat. 2023 Mar 22.
      Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number of underlying mechanisms for anticancer drug resistance including genetic/epigenetic modifications, microenvironmental factors, and tumor heterogeneity. In the present scenario, researchers have focused on these novel mechanisms and strategies to tackle them. Recently, researchers have recognized the ability of cancer to become dormant because of anticancer drug resistance, tumor relapse, and progression. Currently, cancer dormancy is classified into "tumor mass dormancy" and "cellular dormancy." Tumor mass dormancy represents the equilibrium between cell proliferation and cell death under the control of blood supply and immune responses. Cellular dormancy denotes the state in which cells undergo quiescence and is characterized by autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications. Cancer dormancy has been regarded as the stem of primary or distal recurrent tumor formation and poor clinical outcomes in cancer patients. Despite the insufficiency of reliable models of cellular dormancy, the mechanisms underlying the regulation of cellular dormancy have been clarified in numerous studies. A better understanding of the biology of cancer dormancy is critical for the development of effective anticancer therapeutic strategies. In this review, we summarize the characteristics and regulatory mechanisms of cellular dormancy, introduce several potential strategies for targeting cellular dormancy, and discuss future perspectives.
    Keywords:  Anticancer drug resistance; Cancer progression; Cellular dormancy; Dormancy; Neoplasms; Recurrence
  10. Front Endocrinol (Lausanne). 2023 ;14 1144747
      Background: Osteosarcoma is the most common primary bone tumor, its high incidence of metastasis and poor prognosis have led to a great deal of concern for osteosarcoma. In many cancer types, metabolic processes are important for tumor growth progression, so interfering with the metabolic processes of osteosarcoma may be a therapeutic option to stall osteosarcoma progression. A key mechanism of how metabolic processes contribute to the growth and survival of various cancers, including osteosarcoma, is their ability to support tumor cell metabolism. Research related to this field is a direction of great importance and potential. However, to our knowledge, no bibliometric studies related to this field have been published, and we will fill this research gap.Methods: Publications were retrieved on January 1, 2023 from the 1990-2022 Science Citation Index of the Web of Science Core Collection. The Bibliometrix package in R software, VOSviewer and CiteSpace software were used to analyze our research directions and to visualize global trends and hotspots in osteosarcoma and metabolism related research.
    Results: Based on the search strategy, 833 articles were finally filtered. In this area of research related to osteosarcoma metabolism, we found that China, the United States and Japan are the top 3 countries in terms of number of articles published, and the journals and institutions that have published the most research in this area are Journal of bone and mineral research, Shanghai Jiao Tong University. In addition, Baldini, Nicola, Reddy, Gs and Avnet, Sofia are the top three authors in terms of number of articles published in studies related to this field. The most popular keywords related to the field in the last 30 years are "metabolism" and "expression", which will guide the possible future directions of the field.
    Conclusion: We used Bibliometrix, VOSviewer, and Citespace to visualize and bibliometrically analyze the current status and possible future hotspots of research in the field of osteosarcoma metabolism. Possible future hotspots in this field may focus on the related terms "metabolism", "expression", and "migraation".
    Keywords:  bibliometrics; metabolism; osteosarcoma; trends; visualized study
  11. Curr Opin Chem Biol. 2023 Mar 20. pii: S1367-5931(23)00024-8. [Epub ahead of print]74 102286
      Reader domains that recognize methylated lysine and arginine residues on histones play a role in the recruitment, stabilization, and regulation of chromatin regulatory proteins. Targeting reader proteins with small molecule and peptidomimetic inhibitors has enabled the elucidation of the structure and function of specific domains and uncovered their role in diseases. Recent progress towards chemical probes that target readers of lysine methylation, including the Royal family and plant homeodomains (PHD), is discussed here. We highlight recently developed covalent cyclic peptide inhibitors of a plant homeodomain. Additionally, inhibitors targeting previously untargeted Tudor domains and chromodomains are discussed.
    Keywords:  Chemical probes; Lysine methylation; Peptidomimetic ligands; Post-translational modifications; Reader domains; Small-molecule antagonists
  12. J Adv Pharm Technol Res. 2023 Jan-Mar;14(1):14(1): 18-23
      Osteosarcoma is a common primary malignant bone tumor that typically manifests in the second decade of life. This study aimed to identify osteogenic compounds that potentially serve as multitarget inhibitors for osteosarcoma. The study was a molecular docking study of nine Food and Drug Administration-approved compounds with osteogenic properties to the key membrane proteins of osteosarcoma. The ligands used were raloxifene, simvastatin, dexamethasone, risedronate, ibandronate, zoledronic acid, ascorbic acid, alendronate, and β-glycerophosphate, whereas the target proteins used were RET, fibroblast growth factor receptor 1, KIT, PDGFRA, VEGFR1, and VEGFR2. Chem3D version was used for ligand preparation, and AutoDockTools version 1.5.6 was used for protein preparation, whereas molecular docking was conducted using AutoDock Vina. Raloxifene, simvastatin, and dexamethasone had the lowest binding activity to the target proteins. The binding affinity of raloxifene was from -8.4 to -10.0 kcal mol-1, that of simvastatin was -8.3 to -9.2 kcal mol-1, whereas dexamethasone ranged from -6.9 to -9.1 kcal mol-1. Most types of interactions were hydrophobically followed by hydrogen bonding. The current study suggests that raloxifene, simvastatin, and dexamethasone have the potential to act as multitarget inhibitors for osteosarcoma with the ability to induce bone remodeling.
    Keywords:  Bone cancer; cancer; large bone defect; molecular docking; raloxifene; simvastatin
  13. J Biol Chem. 2023 Mar 17. pii: S0021-9258(23)00266-1. [Epub ahead of print] 104624
      Cancer cells experience increased levels of oxidant stress as a consequence of oncogene activation, nucleotide biosynthesis, and growth factor receptor signaling. Mitochondria contribute to this redox stress by generating reactive oxygen species (ROS) along the electron transport chain (ETC), which are released to the matrix and the intermembrane space (IMS). Assessing the contribution of mitochondrial ROS in cancer cells is technically difficult, as ETC inhibitors can increase or decrease ROS generation, while they also block oxidative phosphorylation and ATP synthesis. Mitochondria-targeted antioxidant compounds can scavenge ROS in the matrix compartment, but do not act on ROS released to the intermembrane space. We assessed the importance of mitochondrial ROS for tumor cell proliferation, survival, and for tumor xenograft growth by stably expressing a hydrogen peroxide (H2O2) scavenger, peroxiredoxin-5, in the mitochondrial IMS (IMS-Prdx5) in 143B osteosarcoma and HCT116 colorectal cancer cell lines. IMS-Prdx5 attenuates hypoxia-induced ROS signaling as assessed independently in cytosol and IMS, HIF-1α stabilization and activity, and cellular proliferation under normoxic and hypoxic culture conditions. It also suppressed tumor growth in vivo. Stable expression of non-degradable HIF-1α only partially rescued proliferation in IMS-Prdx5-expressing cells, indicating that mitochondrial H2O2 signaling contributes to tumor cell proliferation and survival through HIF-dependent and HIF-independent mechanisms.
    Keywords:  Hypoxia-Inducible Factor-1; Reactive oxygen species; cancer; mitochondrial intermembrane space; peroxiredoxin-5; redox signaling