bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒07‒30
eight papers selected by
Ankita Daiya
BITS Pilani

  1. Int J Mol Sci. 2023 Jul 16. pii: 11534. [Epub ahead of print]24(14):
      Single cell biology has revealed that solid tumors and tumor-derived cell lines typically contain subpopulations of cancer cells that are readily distinguishable from the bulk of cancer cells by virtue of their enormous size. Such cells with a highly enlarged nucleus, multiple nuclei, and/or multiple micronuclei are often referred to as polyploid giant cancer cells (PGCCs), and may exhibit features of senescence. PGCCs may enter a dormant phase (active sleep) after they are formed, but a subset remain viable, secrete growth promoting factors, and can give rise to therapy resistant and tumor repopulating progeny. Here we will briefly discuss the prevalence and prognostic value of PGCCs across different cancer types, the current understanding of the mechanisms of their formation and fate, and possible reasons why these tumor repopulating "monsters" continue to be ignored in most cancer therapy-related preclinical studies. In addition to PGCCs, other subpopulations of cancer cells within a solid tumor (such as oncogenic caspase 3-activated cancer cells and drug-tolerant persister cancer cells) can also contribute to therapy resistance and pose major challenges to the delivery of cancer therapy.
    Keywords:  anastasis; apoptosis; cancer therapy; intratumor heterogeneity; polyploid giant cancer cells; precision oncology; preclinical assays; senescence
  2. Int J Mol Sci. 2023 Jul 12. pii: 11378. [Epub ahead of print]24(14):
      Somatic heterozygous mutations in the active site of the enhancer of zeste homolog 2 (EZH2) are prevalent in diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). The methyltransferase activity of EZH2 towards lysine 27 on histone H3 (H3K27) and non-histone proteins is dysregulated by the presence of gain-of-function (GOF) and loss-of-function (LOF) mutations altering chromatin compaction, protein complex recruitment, and transcriptional regulation. In this study, a comprehensive multi-omics approach was carried out to characterize the effects of differential H3K27me3 deposition driven by EZH2 mutations. Three stable isogenic mutants (EZH2Y641F, EZH2A677G, and EZH2H689A/F667I) were examined using EpiProfile, H3K27me3 CUT&Tag, ATAC-Seq, transcriptomics, label-free proteomics, and untargeted metabolomics. A discrete set of genes and downstream targets were identified for the EZH2 GOF and LOF mutants that impacted pathways involved in cellular proliferation, differentiation, and migration. Disruption of protein networks and metabolic signatures able to sustain aberrant cell behavior was observed in response to EZH2 mutations. This systems biology-based analysis sheds light on EZH2-mediated cell transformative processes, from the epigenetic to the phenotypic level. These studies provide novel insights into aberrant EZH2 function along with targets that can be explored for improved diagnostics/treatment in hematologic malignancies with mutated EZH2.
    Keywords:  EZH2; epigenetics; histone methylation; multi-omics; mutations
  3. J Transl Med. 2023 Jul 28. 21(1): 512
      Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid-liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear-mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.
    Keywords:  Cytoplasmic translation; LLPS; Mitochondrial translation; OXPHOS; Retrograde signals
  4. Cell Biosci. 2023 Jul 25. 13(1): 136
      BACKGROUND: The absence of prominent, actionable genetic alternations in osteosarcomas (OS) implies that transcriptional and epigenetic mechanisms significantly contribute to the progression of this life-threatening form of cancer. Therefore, the identification of potential transcriptional events that promote the survival of OS cells could be key in devising targeted therapeutic approaches for OS. We have previously shown that RUNX2 is a transcription factor (TF) essential for OS cell survival. Unfortunately, the transcriptional network or circuitry regulated by RUNX2 in OS cells is still largely unknown.METHODS: The TFs that are in the RUNX2 transcriptional circuitry were identified by analyzing RNAseq and ChIPseq datasets of RUNX2. To evaluate the effect of SOX9 knockdown on the survival of osteosarcoma cells in vitro, we employed cleaved caspase-3 immunoblotting and propidium iodide staining techniques. The impact of SOX9 and JMJD1C depletion on OS tumor growth was examined in vivo using xenografts and immunohistochemistry. Downstream targets of SOX9 were identified and dissected using RNAseq, pathway analysis, and gene set enrichment analysis. Furthermore, the interactome of SOX9 was identified using BioID and validated by PLA.
    RESULT: Our findings demonstrate that SOX9 is a critical TF that is induced by RUNX2. Both in vitro and in vivo experiments revealed that SOX9 plays a pivotal role in the survival of OS. RNAseq analysis revealed that SOX9 activates the transcription of MYC, a downstream target of RUNX2. Mechanistically, our results suggest a transcriptional network involving SOX9, RUNX2, and MYC, with SOX9 binding to RUNX2. Moreover, we discovered that JMJD1C, a chromatin factor, is a novel binding partner of SOX9, and depletion of JMJD1C impairs OS tumor growth.
    CONCLUSION: The findings of this study represent a significant advancement in our understanding of the transcriptional network present in OS cells, providing valuable insights that may contribute to the development of targeted therapies for OS.
    Keywords:  Epigenetics; JMJD1C; Osteosarcoma; RUNX2; SOX9; Transcription
  5. J Biol Chem. 2023 Jul 25. pii: S0021-9258(23)02108-7. [Epub ahead of print] 105080
      Epigenetic repression often involves covalent histone modifications. Yet, how the presence of a histone mark translates into changes in chromatin structure that ultimately benefit the repression is largely unclear. Polycomb group proteins comprise a family of evolutionarily conserved epigenetic repressors. They act as multi-subunit complexes one of which tri-methylates histone H3 at Lysine 27 (H3K27). Here we describe a novel Monte Carlo - Molecular Dynamics simulation framework, which we employed to discover that stochastic interaction of the Polycomb Repressive Complex 1 (PRC1) with tri-methylated H3K27 is sufficient to fold the methylated chromatin. Unexpectedly, such chromatin folding leads to spatial clustering of the DNA elements bound by PRC1. Our results provide further insight into mechanisms of epigenetic repression and the process of chromatin folding in response to histone methylation.
    Keywords:  Drosophila; Polycomb; chromatin structure; epigenetics; histone methylation
  6. Front Oncol. 2023 ;13 1177466
      Drug resistance in tumours has seriously hindered the therapeutic effect. Tumour drug resistance is divided into primary resistance and acquired resistance, and the recent study has found that a significant proportion of cancer cells can acquire stable drug resistance from scratch. This group of cells first enters the drug tolerance state (DT state) under drug pressure, and gradually acquires stable drug resistance through adaptive mutations in this state. Although the specific mechanisms underlying the formation of drug tolerant cells (DTCs) remain unclear, various proteins and signalling pathways have been identified as being involved in the formation of DTCs. In the current review, we summarize the characteristics, molecular mechanisms and therapeutic strategies of DTCs in detail.
    Keywords:  cancer; characteristics; drug tolerance; molecular mechanisms; therapeutic strategies
  7. Cancer Discov. 2023 Jul 28. OF1
      Intrinsic variability within homogeneous cancer populations generates diverse drug resistant clones.
  8. Trends Cancer. 2023 Jul 25. pii: S2405-8033(23)00130-9. [Epub ahead of print]
      Epigenetically mediated cell signaling is emerging as a core principle of tumor biology. Through single cell multi-omic profiling, Burdziak, Alonso-Curbelo et al. have recently uncovered key epigenetic plasticity programs associated with cellular communication, shedding light on the role of epigenetic cell states during malignant transformation of the inflamed pancreas.